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Immunotherapy of Multiple Myeloma: Current Status as Prologue to the Future

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Submitted:

15 September 2023

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19 September 2023

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Abstract
The landscape of therapeutic measures to treat multiple myeloma has undergone a seismic shift since the dawn of the current century. This has been driven largely by the introduction of new classes of small molecules, such as proteasome blockers (e.g., bortezomib) and immunomodulators (e.g., lenalidomide), as well as by immunotherapeutic agents starting with the anti-CD38 monoclonal antibody daratumumab in 2015. Recently, other immunotherapies have been added to the armamentarium of drugs available to fight this malignancy. These include the bispecifics teclistamab, talquetamab, and elranatamab, and the chimeric antigen receptor (CAR) T-cell products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). While the accumulated benefits of these newer agents have resulted in a more than doubling of the disease’s five-year survival rate to nearly 60% and improved quality of life, the disease remains incurable, as patients become refractory to the drugs and experience relapse. This review covers the current scope of anti-myeloma immunotherapeutic agents, both those in clinical use and in development. Included in the discussion are additional monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), bi- and multi-targeted mAbs, and CAR T-cells and emerging natural killer (NK) cells, including products intended for “off-the-shelf” (allogeneic) applications. Emphasis is placed on the benefits of each along with the challenges that need to be surmounted if MM is to be cured.
Keywords: 
Subject: Medicine and Pharmacology  -   Hematology

1. Introduction

Multiple myeloma (MM) is a hematologic cancer characterized by clonal proliferation of plasma cells in bone marrow, as well as by high levels of monoclonal immunoglobulins in blood and/or urine [1]. As a blood cancer, the disease ranks second in the United States behind non-Hodgkin’s lymphoma (NHL) and 14th among all cancers in terms of incidence. Based on current estimates, in 2023 MM will be diagnosed in 35,730 individuals (55.6% male) and will be responsible for 12,590 deaths in the U.S. [2]. The median age at diagnosis in the U.S. is 69 [3]. Worldwide, in 2020 there were an estimated 176,404 cases of the disease (0.9% of all cancers) accounting for 117,077 deaths (1.2% of cancer deaths) [4]. Substantial racial disparities have been noted for all stages of MM in the U.S. For example, in the 2014-2018 period, the incidence of MM per 100,000 population in African Americans was more than double that in Caucasians (16.7 vs. 7.8 for males and 12.3 vs. 4.8 for females) [5]. Guidelines for the diagnosis and treatment of MM are updated and published annually by the National Comprehensive Cancer Network (NCCN) [6]. While the cause of MM is not established, cytogenetic factors are known to play a significant role in certain MM patients classified as “high risk”. Among the most frequently observed of these variances are the chromosomal deletion del(17p) and the transversions t(4;14) and t(14;16) [7].
An active case of MM typically includes a quartet of symptoms known by the acronym CRAB: hypercalcemia, renal insufficiency, anemia, and bone lesions. An asymptomatic state, monoclonal gammopathy of undetermined significance (MGUS) often precedes an active case [8]. The risk of progression from MGUS to MM has been estimated at about 1% per year [9]. Smoldering multiple myeloma (SMM), a second asymptomatic phase, also has been described although its significance relative to MM has been a matter of continuing controversy [10].
Alkylating agents (melphalan and/or cyclophosphamide), often in combination with corticosteroids, were the treatment of choice for MM starting in the 1950s. This standard regimen was augmented by autologous stem cell transplantation (ASCT) in the mid-1980s. The picture began to change in the late 1990s with the discovery of the anti-myeloma effects of thalidomide and later of its two chemically related derivatives, lenalidomide and pomalidomide. Furthermore, the first two decades of the current century were marked by the discovery of the anti-myeloma benefits of two entirely new classes of small molecules - proteasome inhibitors (bortezomib, carfilzomib, and ixazomib) and blockers of nuclear export (selinexor).
A paradigm shift in the therapeutic approach to MM occurred in 2015 with the approval of two monoclonal antibodies, daratumumab and elotuzumab, for the disease. This review covers the fundamental aspects of MM immunotherapy, highlighting the remarkable advances made in this arena over the past decade and features discussion of currently approved agents, as well as those in various stages of development. For information on the background, history, and current status of immunotherapeutic applications in cancer treatment, the reader is directed to the recent reviews of Liu [11] and Anagnostou [12].

2. Monoclonal Antibodies Targeting CD38

The 45 kDa transmembrane glycoprotein CD38 has elicited considerable interest as a major target in MM. This biomarker, which is expressed at high levels in both normal and neoplastic plasma cells, as well as at lower levels in other blood cells, is known to perform several functions in the cell. Its primary role appears to result from its cyclic ADP ribose hydrolase activity, the products of which are important regulators of intracellular calcium levels. The lethality of anti-CD38 antibodies to myeloma cells is due to a combination of antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC) [13].
Since its approval by the U.S. Food and Drug Administration (FDA) as the first immunotherapeutic agent for MM, daratumumab, a fully human IgG1k monoclonal antibody (mAb) that targets CD38+ cells, has assumed a prominent role in treatment of the disease. According to NCCN guidelines, the combination of daratumumab with lenalidomide, bortezomib, and dexamethasone is considered a major recommendation in newly diagnosed multiple myeloma (NDMM) for patients regardless of transplant eligibility status. Additionally, daratumumab-dexamethasone triplet regimens that include either lenalidomide or bortezomib are primary recommendations in cases of refractory and/or relapsed multiple myeloma (RRMM). A number of network meta-analytic studies of random-controlled trials may be cited as recent examples that serve to support the application of daratumumab as a major player in a number of myeloma-based settings [14,15,16,17,18]. Moreover, the recently approved subcutaneous (sc) formulation of daratumumab combined with hyaluronidase provides the substantial benefit of enabling markedly shorter administration times: 3–5 minutes vs. several hours of intravenous (iv) infusion without compromising efficacy or patient safety [19]. HLX15, a daratumumab biosimilar developed in China recently entered a phase II clinical trial designed to compare its properties with those of daratumumab in normal male subjects (NCT05679258).
Infusion reactions, which include rash, headache, cough, nausea, vomiting, nasal congestion, and dyspnea, represent an adverse but usually low-grade reaction to daratumumab, being noted in up to 50% of patients receiving the drug, especially during the first two infusions. Prior administration of a glucocorticoid and/or a leukotriene blocker (e.g., montelukast) may help diminish this effect and may be especially useful in patients with underlying respiratory disease [20]. In addition, daratumumab can interfere with blood typing by binding to CD38 on reagent blood cells, resulting in a positive indirect Coombs test. This can be circumvented by performing blood-typing procedures prior to using daratumumab [21]. Daratumumab use may also result in infections primarily resulting from bone marrow suppression. This may necessitate use of prophylactic antimicrobials such as cotrimoxazole to prevent Pneumocystis jiroveci pneumonia.
Isatuximab (SAR650984), a second anti-CD38 mAb, was introduced for MM in 2020. The mechanism of action of this chimeric IgG1k mouse-human construct is similar to that of daratumumab, although isatuximab binds to an epitope distinct from that which binds daratumumab [22]. Isatuximab was approved initially for intravenous use with pomalidomide and dexamethasone in patients who had relapsed following at least two prior therapies that included a proteasome inhibitor and lenalidomide [23]. Data from the phase III ICARIA trial, in which addition of isatuximab to a pomalidomide/dexamethasone regimen in RRMM subjects resulted in significantly longer progression-free survival (PFS) (11.5 months vs. 6.5 months), served as basis for this approval [24]. Subsequently, replacement of the immunomodulator in this triplet therapy by the proteasome blocker carfilzomib was sanctioned for use in RRMM patients who had received as few as one to three prior regimens. Approval in the latter case was based on the PFS, duration of response, and safety data provided by the phase III IKEMA trial (NCT03275285) [25,26]. Infusion-related reactions, fatigue, hypertension, diarrhea, and upper respiratory tract infections are among the most common adverse reactions noted with isatuximab. The efficacy of subcutaneous administration of isatuximab in regimens containing pomalidomide and dexamethasone is currently under study in two clinical trials: NCT04045795 (phase I, N = 56) [27,28,29] and NCT05405166 (phase III, N = 534). In addition, a recently initiated phase II trial (NCT05704049; N = 68) is investigating the potential role of subcutaneous isatuximab in a carfilzomib/dexamethasone regimen in RRMM patients.

3. Monoclonal Antibodies Targeting SLAMF7

The signaling lymphocytic activation molecule family (SLAMF) comprises a group of transmembrane glycoproteins that is highly expressed almost exclusively on the surface of plasma cells from both normal and MM patients, as well as on natural killer (NK) cells. One member of this family, SLAMF7 (CS1), has emerged as a major target in the search for new immunological products with anti-myeloma activity [30]. The most promising of these agents, the anti-SLAMF7 humanized IgG1k mAb elotuzumab, was approved for use in combination with lenalidomide-dexamethasone in RRMM patients who had relapsed following one to three prior therapies. Approval of elotuzumab, which unlike the anti-CD38 mAbs described above lacks single agent activity against the disease, followed analysis of results of the ELOQUENT-2 trial (NCT01239797) that included 646 patients who were randomly assigned to receive elotuzumab-dexamethasone (Ed) with or without lenalidomide (R). A 30% reduction in the risk of death or disease progression was found for the ERd cohort after one year [31]. Subsequent multi-year follow-up data confirmed the efficacy of this triplet regimen for RRMM [32,33,34]. Further evidence of the benefits of combining Ed treatment with an immunomodulator was provided by the ELOQUENT-3 trial (NCT02654132), which included pomalidomide in patients refractory to both lenalidomide and a proteasome inhibitor [35]. Accordingly, the elotuzumab-dexamethasone-pomalidomide regimen received FDA sanction in 2018 for the treatment of RRMM patients who had received at least two prior therapies that included these two agents. Trials combining elotuzumab-dexamethasone with the proteasome inhibitors bortezomib [36] or carfilzomib [37] in RRMM, although demonstrating significant efficacy, to date have failed to reach the level of favorable outcomes of the scale attained with elotuzumab-immunomodulator combinations. Initial efforts aimed at developing a subcutaneous dosage form of elotuzumab have been described [38].

4. Antibody-Drug Conjugates

A number of antibody-drug conjugates (ADCs), drugs in which an antibody is covalently linked to a toxin or radionuclide, have emerged in the past decade to play an important role in the therapy of certain types of cancer, such as breast and cervical cancers, acute leukemias, and Hodgkin’s disease and other types of lymphoma. ADC construction is predicated on three components: 1) an antibody which targets a tumor-specific or tumor-associated antigen (TSA or TAA), 2) a small cytotoxic molecule (the payload), and 3) a linker to attach the payload to the antibody. Endocytosis of the ADC and subsequent lysosomal cleavage releases the payload to initiate apoptosis of the cancer cell. The antibodies used are generally of the IgG1 class since they demonstrate potent capacity to activate ADCC and ADCP by specific FcgRIIIa binding to NK cells [39]. This binding is further enhanced by removal of fucosyl groups (afucosylation) from the N-linked biantennary complex oligosaccharides in the antibody’s Fc region [40]. The linkers used may be either cleavable or non-cleavable. The former includes chemical functionalities such as hydrazones, disulfides, and peptides, which employ a specific enzymatic property inherent to the tumor cell, while the latter group depends on complete lysosomal degradation of the antibody to cause release of both payload and linker [41,42].
B-cell maturation antigen (BCMA; CD269; TNFRSF17), a 184-amino acid transmembrane glycoprotein belonging to the tumor necrosis family (TNF), has emerged recently as a highly attractive TAA in the quest for new agents to treat MM. This interest is driven by reports that both BCMA and its mRNA transcript are almost exclusively confined to plasma cells and are overexpressed consistently during malignant transformation to myeloma in both patient samples and cell lines [43]. Moreover, there is much evidence indicating that membrane-bound BCMA is a reliable biomarker for MM diagnosis and prognosis, as well as a predictor of response to treatment [44]. On the other hand, although BCMA acts as a ligand for BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand), inhibitors of these two cytokines, which play key roles in myeloma cell proliferation and viability, have demonstrated poor results in MM trials [45,46,47].
The extracellular domain of membrane-bound BCMA may be cleaved by g-secretase resulting in release of soluble BCMA (sBCMA) into the plasma, high levels of which have been correlated with poor clinical outcomes in MM patients. sBCMA not only is an indicator of reduced density of the membrane-bound target antigen BCMA but also serves as a soluble decoy to reduce the efficacy of anti-BCMA agents [48,49]. It is for this reason that orally effective g-secretase inhibitors, such as nirogacestat and crenigacestat, have been included in clinical trials of some newer anti-BCMA drugs [50].
The first and thus far only ADC approved for MM is belantamab mafodotin (Blenrep®, belamaf, GSK2857916), an afucosylated humanized BCMA-targeted antibody that is coupled to the tubular polymerization blocker monomethyl auristatin F (MMAF, mafodotin) by a non-cleavable maleimidocaproyl linker. Initial FDA approval in 2020 of belantamab mafodotin was provided on an accelerated basis for use as monotherapy in RRMM patients who had received at least four earlier regimens, including an anti-CD38 mAb, a proteasome inhibitor, and an immunomodulator [51,52]. Approval was based on data from the DREAMM-2 trial (NCT03525678), which included a total of 196 RRMM patients, receiving the drug as a single agent divided into two dosage groups: 2.5 mg/kg (N = 97) and 3.4 mg/kg (N = 99). Overall response rate (ORR) and PFS data recorded for the two cohorts was 31% and 2.9 months and 34% and 4.9 months, respectively [53]. However, the FDA-required follow-up confirmatory trial (DREAMM-3; NCT04162210) in which belantamab mafodotin monotherapy was compared against pomalidomide/dexamethasone failed to demonstrate improvement in PFS and the approval was withdrawn in Nov. 2022 [54]. Nevertheless, a number of trials in the DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) series that include comparisons of belantamab mafodotin with established anti-myeloma therapies remain active (see Table 1).
Blood cell dyscrasias, such as anemia and thrombocytopenia, were among the most commonly noted adverse effects associated with the use of belantamab mafodotin in the DREAMM-2 trial, as well as in the precursor phase I study. However, the most serious toxic effect accompanying use of this ADC has been the corneal microcyst-like epithelial changes (MECs) first reported in 72% (68/95) of DREAMM-2 patients [74]. This effect, which is not subject to corticosteroid relief but may be reversed by dose reduction [75], has been consistently observed in other studies of not only this but other MMAF-containing ADCs, although its mechanism is unknown [76,77,78,79]. Consequently, initial FDA approval of belantamab mafodotin was accompanied by a Boxed Warning requirement, stating that changes in the corneal epithelium may result in vision loss, corneal ulcers, blurred vision, and dry eyes. As a result, the drug is available only under a restricted Risk Evaluation and Mitigation Strategy (REMS) program, which remains applicable to patients receiving the drug under the provisions of compassionate use.
a-Amanitin, a highly toxic bicyclic octapeptide produced by Amanita phalloides (“death cap mushroom”) recently has emerged as a cytotoxin exhibiting a novel mode of action among ADCs, viz, inhibition of RNA polymerase II [80]. HDP-101, an ADC consisting of an a-amanitin analog conjugated to a BCMA-targeted antibody by a cathepsin B-cleavable linker, currently is the subject of a phase I safety-assessment trial (NCT04879043) in RRMM patients. Initial results on the first cohort of patients showed the drug to have good tolerability in late-stage disease [81].
Another BCMA-targeted ADC of current interest is AMG 224, an afucosylated IgG1 mAb coupled to the microtubule blocker mertansine through a maleimidocaproyl non-cleavable linker. An initial report from a phase I trial (NCT02561962) of AMG 224 showed an ORR of 23% in 40 heavily pretreated RRMM subjects [82]. CC-99712, bearing a maytansinoid payload through a non-cleavable dibenzocyclooctyne linker, is another BCMA-targeted ADC now included in an active myeloma-based trial that also incorporates a g-secretase inhibitor (NCT04036461). However, no data have yet been reported for this study. Besides BCMA, a number of other myeloma-associated targets have served as the basis for formulation of novel ADCs now in clinical development. These are shown in Table 2. In addition, clinical trials of some ADCs that once appeared promising for RRMM have been halted for a variety of reasons, such as poor activity, unacceptable toxicity, and/or undisclosed sponsor decision factors. These include (target in parentheses) MEDI2228 (BCMA), azintuxizumab vedotin (SLAMF7), lorvotuzumab mertansine (CD56), and DFRF4539A (FcRH5).

5. Bispecific Antibodies

T-cell-based immunotherapeutic approaches to cancer have risen to a position of great prominence in recent years. In particular, two specific areas of research have dominated this field: T-cell-engaging bi-specific antibodies (T-BsAbs) and chimeric antigen receptor (CAR) T-cell therapies. The former will be described in this section while discussion of the latter will be reserved for the following segment.
Predicated on a concept originally proposed in 1961 by Nisonoff [91], T-BsAbs are based on the construction of a dual-targeting antibody in which one arm initially attaches to the T-cell CD3 co-receptor, enabling subsequent binding of a second arm to a TSA or TAA on the targeted cancer cell. Although the concept has a multitude of variations, the basic strategy whereby cytotoxic T-cells become tethered to tumor cells results in the latter’s cytolysis. Cell killing is attributed to the combined effects of two proteins: perforin, which produces transmembrane pores in tumor cells, and granzyme B, which travels through the thus-formed channels to activate apoptosis [92].
Bispecific antibodies provide certain theoretical advantages by precluding the need for antigen-presenting cells, co-stimulatory molecules or interaction between an antigen and a major histocompatibility complex (MHC) molecule. Moreover, the persistent T-cell activation permits polyclonal expansion of T memory cells. Also, such constructs, by obviating any requirement for ex vivo T-cell manipulation, make “off-the shelf” products feasible. Importantly, each arm’s relative affinity for its specific target is subject to modification thus permitting fine-tuning of each construct’s therapeutically relevant properties to optimize biopharmaceutic parameters and activity [93,94,95,96].
The Bi-specific T-cell Engager (BiTE®) platform represents an application of the bi-specific concept in which two single-chain variable fragments (scFvs) arranged in tandem provide the cross-link between the T-cell CD3 co-receptor and a tumor cell TSA or TAA. Originally developed by Micromet AG (now a subsidiary of Amgen), BiTE® technology was first successfully applied to cancer therapy with the approval in 2014 of blinatumomab for B-cell precursor acute lymphocytic leukemia (B-cell ALL). The scFv cross-link in this product is provided between T-cell CD3 and tumor cell lymphocyte antigen CD19 although studies seeking to extend this model to myeloma cell CD19 as a suitable binding partner have proven much less successful. On the other hand, BCMA has demonstrated itself to be most worthy of exploration as a CD3 linkage companion. Success in this space was attained with FDA’s authorization of the IgG4-based teclistamab (Tecvayli®) in Oct. 2022 as the first CD3 x BCMA bispecific for RRMM. Approval, which was granted for subcutaneous use in patients who had received at least four lines of therapy, was based on evaluation of data from the MajesTEC-1 trial (NCT03145181; NCT04557098). This study revealed an ORR of 63.0% (104/165) and a median PFS of 11.3 months in the 128 (77.6%) subjects classed as triple-class refractory. Notably, 44 (26.7%) of evaluated patients gave no evidence of minimal residual disease (MRD). The most common adverse effects observed were cytokine release syndrome (CRS) (72.1%), neutropenia (70.9%), anemia (52.1%), thrombocytopenia (40.0%), and neurotoxicity (14.5%). In addition, infections were noted in 76.4% of the patients [97]. Several of the currently active trials of teclistamab are shown in Table 3.
In Aug. 2023, the IgG2a construct elranatamab (Elrexfio®; PF-06863135), another CD3 x BCMA bispecific that has emerged in this class, was granted accelerated approval as monotherapy by the FDA [109]. This action was spurred by the results from the MagnetisMM-3 trial (NCT04649359) in which an ORR of 61.0% and a complete response rate of 35.0% were reported in a cohort of 123 RRMM subjects after a median follow-up of 14.7 months [110]. Table 4 contains a listing of several ongoing clinical trials in which elranatamab is under evaluation.
An alternative strategy for developing bispecifics targeting BCMA is represented by receptors on NK cells, which like cytotoxic T-cells release granzyme and perforin, as well as certain apoptosis-inducing ligands [117]. A prominent example here is RO7297089 (AFM26), which engages myeloma cell BCMA and NK CD16A and is currently the subject of a phase I trial for RRMM (NCT04434469). An initial report on 27 patients found the drug to be well tolerated although efficacy was weak with only 4 subjects evidencing partial or minimal responses [118].
In addition to the bispecifics noted above, several other variations based on the CD3 x BCMA theme now are under development. These include (see Table 5 for clinical trials incorporating these and related agents):
Linvoseltamab (REGN5458) and REGN5459 – this pair of IgG4k-based CD3 x BCMA bispecifics developed using Regeneron’s VelocImmune® “human antibody mouse” technology differ primarily in their binding characteristics with the CD3 arm [119].
EMB-06: a tetravalent CD3 x BCMA bispecific antibody in which two antigen-binding fragments are fused in a crisscross fashion, referred to as a Fabs-In-Tandem-Ig format, to generate four independently active antigen binding sites [120].
Alnuctamab (CC-93269): a trivalent T-cell engager in which one arm binds to CD3ε while the other two arms attach bivalently to BCMA [121].
HPN217 developed by Harpoon Therapeutics, is another example of a tri-specific engager. In this case, the molecule consists of three binding domains in a single chain: a BCMA-binding component at the N-terminus, a CD3ε T-cell receptor (TCR) binding domain at the C-terminus, and a central human serum albumin-binding portion. This product’s smaller size and flexibility are thought to account for its pro- longed half-life [122].
ABBV-383 (TNB-383B) a collaborative effort between AbbVie and Tenebio, is comprised of a single light chain domain and two variable heavy chains in a BCMA x CD3 format. Its strong T-cell activation kinetics and low-affinity anti-CD3ε arm are said to be responsible for the reduced level of cytokine release without diminishing cytotoxicity [123].
WVT078 – A CD3 x BCMA IgG1 construct with an IgG1 backbone containing Fc mutations designed to favor pairing of the two distinct heavy chains [124].
Table 5. Selected Active Trials of Additional CD3 x BCMA Targeting Bispecific Antibodies in Multiple Myeloma (MM).
Table 5. Selected Active Trials of Additional CD3 x BCMA Targeting Bispecific Antibodies in Multiple Myeloma (MM).
Trial ID (References) Drugs Phase Enrollment (N) Trial Title
NCT05650632 ABBV-383 I 80 Multicenter, Open-label Study to Evaluate Dose Optimization Measures and Safety of ABBV-383 in Subjects With RRMM
NCT05259839 [125] ABBV-383 + various anti-myeloma agents I 270 Dose Escalation and Expansion Study of ABBV-383 in Combination With Anti-Cancer Regimens for the Treatment of Patients With RRMM
NCT04735575 EMB-06 I/II 66 First-in-human, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of EMB-06 in Patients With RRMM
NCT03486067 [126] Alnuctamab (CC-93269) I 220 Open-label, Dose Finding Study of CC-93269, a BCMA x CD3 T Cell Engaging Antibody, in Subjects With RRMM
NCT05828511 Linvo (REGN5458) I/II 132 Study of Linvoseltamab (Anti-BCMA X Anti-CD3 Bispecific Antibody) in Previously Untreated Patients With Symptomatic MM
NCT05730036 Elo+ Pom + Dex +/- III 286 Open-label, Randomized Study of Linvoseltamab (REGN5458; Anti- BCMA x Anti-CD3 Bispecific Antibody) Versus the Combination of Elotuzumab, Pomalidomide, and Dexamethasone (EPd), in Patients With RRMM (LINKER-MM3)
NCT05137054 Linvo + various anti-myeloma agents Ib 317 Study of REGN5458 (Anti-BCMA x Anti-CD3 Bispecific Antibody) Plus Other Cancer Treatments for Patients With RRMM
NCT03761108 [127,128,129] Linvo I/II 309 FIH Study of REGN5458 (Anti-BCMA x Anti-CD3 Bispecific Antibody) in Patients With RRMM
NCT04083534 [130] REGN5459 I/II 43 FIH Study of REGN5459 (Anti-BCMA x Anti-CD3 Bispecific Antibody) in Patients With RRMM
NCT03933735 [131] TNB-383B I/II 220 Multicenter Open-label, Dose-escalation and Expansion Study of TNB-383B, a Bispecific Antibody Targeting BCMA in Subjects With RRMM
NCT05646758 TQB2934 I 140 Clinical Trial Evaluating the Tolerance and Pharmacokinetics of TQB2934 for Injection in MM Subjects
NCT04123418 [124] WVT078 I 56 Open-label, Multicenter, Study of WVT078 in Subjects With RRMM
NCT04184050 [132] HPN217 I 70 Open-label, Multicenter, Dose Escalation Study of the Safety, Tolerability, and Pharmacokinetics of HPN217 in Patients With RRMM
Dex = dexamethasone; Elo = elotuzumab; FIH = first in humans; Linvo = linvoseltamab; MM = multiple myeloma; Pom = pomalidomide; RRMM = relapsed and/or refractory MM .
Surface antigens other than BCMA also have served as targets for discovery of anti-myeloma bispecific antibodies. One that has risen to prominence in recent years is GPRC5D (G-protein-coupled receptor, class C, group 5, member D). This orphan receptor is known to be expressed primarily on the surface of myeloma cells, as well as on hard-keratinized tissues [133], and is associated with poor prognosis in MM [134]. In Aug. 2023, the FDA granted accelerated approval to talquetamab (Talvey®) a GPRC5D x CD3 bispecific [135], based on the results of the MonumenTAL-1 trial (NCT03399799, NCT4634552) in which ORRs of 73.0% and 73.6% were obtained in respective cohorts receiving subcutaneous doses of either 0.4 mg/kg weekly (N = 100) or 0.8 mg/kg biweekly (N = 87). Table 6 shows the current ongoing trials of talquetamab in RRMM patients.
Forimtamig (RG6234; RO7425781), a second CD3 x GPRC5D bispecific that has shown potential anti-myeloma efficacy in preclinical studies [144] recently was advanced to a clinical study for the disease (NCT04557150). Initial results from a phase I dose-escalation investigation demonstrated that iv administration of this agent was somewhat more effective than sc use [iv: ORR = 71.4% (35/49) vs. sc: 60.4% (29/48)] [145].
Another non-BCMA target is FcRH5, which is expressed on virtually all malignant plasma cells [146]. The major entrant in this area is cevostamab (BFCR4350A; RO7187797), designed to bind T-cell CD3 with the most membrane-proximal domain of FcRH5 and currently the subject of six clinical trials for RRMM (see Table 7). It is noteworthy that each of these trials incorporates tocilizumab, which has been demonstrated to reduce cytokine release syndrome when given prior to cevostamab [147].
Included among other non-BCMA directed constructs presently under consideration for RRMM are:
ISB 1342 (GBR 1342), a CD3 x CD38 bispecific (NCT03309111) [151,152].
VP301, a CD38 x ICAM-1 bispecific (NCT05698888); ICAM-1 (intercellular adhesion molecule-1; CD54), an adhesion molecule highly expressed on transformed plasma cells and associated with anti-myeloma drug resistance [153,154].
ISB 1442 (NCT05427812), a tri-specific which engages both CD38 and CD47 on myeloma cells [155,156].
SAR442257, another tri-specific (CD38/CD28 x CD3) (NCT04401020) [157].
A recent systematic analysis of 18 RRMM-based studies (1283 total patients) involving bispecific antibodies found that the 13 studies that included BCMA-targeting agents had ORRs ranging from 25% to 100% while the 5 studies that involved non-BCMA targeting agents had ORRs that ranged between 60% and 100%. Also, comparison of rates of complete responses (or stringent complete responses) tended to favor bispecifics directed against targets other than BCMA: 19-63% vs. 7-38% [158].

6. CAR T-Cells

The past decade has witnessed the emergence of chimeric antigen receptor (CAR) T-cell therapy as an immunotherapeutic approach of immense importance in the treatment of various cancers [159,160]. As a mode of adoptive cell transfer (ACT), this strategy employs recombinant DNA technology using a viral vector to genetically modify a patient’s own cytotoxic T-cells, enabling eventual expression of a chimeric receptor specifically targeting a TAA or TSA almost exclusively confined to a given type of malignant cell. CAR T-cells typically consist of the target-directed ectodomain (usually a scFv), a transmembrane component, a hinge region, and costimulatory signaling endodomains, such as CD28 or 4-1BB [161]. The thusly engineered T-cells then can be reinfused back into the patient resulting in T-cell engagement with the targeted cancer cells resulting in their death. This tactic has been most successfully used in hematological cancers, especially B-cell malignancies where CD19 is the intended target although, as noted earlier, myeloma cell CD19 per se has not been demonstrated to be particularly amenable as an immunotherapeutic target. For example, a study of tisagenlecleucel, an anti-CD19 CAR, combined with ASCT and melphalan, provided poor clinical benefit to a group of ten MM subjects (NCT02135406) [162]. However, an exception to this may be seen with CARs that target both CD19 and BCMA - see discussion of GC012F (below).
Some early trials involving anti-CD19 CAR T-cell therapy were confounded by the finding that durable remissions were difficult to obtain in spite of initial ORRs often exceeding 80% [163,164,165,166]. This issue was resolved eventually when the benefits of including lymphodepletion, usually consisting of combined fludarabine/ cyclophosphamide, in the pre-ACT regimen [167]. The mechanism underlying the enhanced T-cell expansion and persistence, as well as the more favorable clinical outcomes, associated with lymphodepletion remain obscure.
In common with several of the drugs discussed above, BCMA also plays a concentrated role as a TAA of intense interest in anti-myeloma CAR T-cell research. The first CAR T-cell product to receive FDA approval for MM (March 2021) was Bluebirdbio’s idecabtagene vicleucel (Abecma®; bb2121; ide-cel) [168]. This anti-BCMA construct employed a lentivirus-engineered template in which the anti-BCMA scFv was linked serially to a CD8 hinge, a transmembrane region, a CD28 co-stimulatory domain and CD3ζ served as the T-cell activator. Approval focused on the results of the KarMMa-1 (NCT03361748) trial that included 128 RRMM patients who had failed at least three prior standard regimens. Of the 128 patients receiving the drug, a 73% ORR was seen and 42 (33%) experienced complete responses or better. A median PFS of 8.8 months was recorded. CRS was reported in 84% of subjects (5% of grades 3 or higher) while neurotoxicity was observed in 16% (3% grade 3; 0 grade 4 or higher) [169]. Further encouraging outcomes were seen in a recent RRMM phase III study (NCT03651128; KarMMa-3) that compared two cohorts of RRMM patients (2-4 prior regimens), one of which received ide-cel (N = 254) while the other (N = 132) was given one of five standard MM regimens. After 18.6 months of follow-up a median PFS of 13.3 months was observed in the ide-cel group vs. 4.4 months in the group receiving standard courses of therapy. Toxicity in the ide-cel cohort was similar to that seen in the KarMMa-1 study [170]. Ide-cel’s sponsor (Bristol Myers Squibb) recently filed applications with the FDA and European Medicines Agency (EMA), as well as in Japan, to enable the agent to be used in triple-, instead of the originally sanctioned quadruple-, class exposed RRMM patients [171]. Action on these applications remains pending as of this writing.
In Feb. 2022, the FDA approved a second BCMA-targeted CAR T-cell therapeutic for RRMM - ciltacabtagene autoleucel (Carvykti®, JNJ-68284528; LCAR-B38M; cilta-cel). Approval was supported by the results of the CARTITUDE-1 trial (NCT03548207) in which 97 patients with at least three prior lines of therapy achieved an ORR of 97% and 67% stringent complete responses. After 12 months PFS and overall survival (OS) rates of 77% and 89%, respectively, were reported. CRS was noted in 95% of the study subjects (4% grade 3 or higher) while neurotoxicity was observed in 21% [172]. The results of a phase III trial (NCT04181827; CARTITUDE-4) that studied lenalidomide-refractory patients provided further evidence of the effectiveness of cilta-cel in RRMM patients [173]. This study compared one cohort (N = 208) which received a single injection of cilta-cel with a second group (N = 211) which received only standard care. The PFS of the first cohort after 12 months was 75.9% vs. 48.6% in the second group while the ORRs were 84.6% and 67.3%, respectively. Significantly, patients in the study group demonstrated MRD negativity to a much higher degree (60.6% to 15.6%) than those who received standard therapy.
Equecabtagene autoleucel (Fucaso®; CT103A), another BCMA-targeted CAR T-cell therapy, was designated an RMAT (Regenerative Medicine Advanced Therapy) agent by the FDA in 2023, the same year in which it was approved for RRMM by China’s National Medical Products Administration (NMPA). The application for approval was supported by data from the phase I/II FUMANBA-1 trial (NCT05066646; CTR20192510), which found that the agent elicited an ORR of 96% in 101 evaluable subjects, including complete responses or better in 74.3% and a 12-month PFS rate of 78.8% [174].
Other autologous anti-BCMA CAR T-cell products currently under development include (see Table 8):
Zevorcabtagene autoleucel (zevo-cel; CT053): received an RMAT designation for RRMM treatment from the FDA in 2019. One study (NCT03975907) of patients with at least three prior therapies reported an ORR of 100% in 14 subjects [175].
CC-98633 (BMS-986354): manufactured using the NEX-T process, which combines shortened manufacturing time with improved potency and phenotypic attributes to enhance depth and durability of response [176]. This product is similar in construction to orvacabtagene autoleucel (orva-cel), a once-promising product that is no longer being pursued by its sponsor.
PHE885: A construct manufactured using the proprietary Novartis T-Charge platform, which is said to enable patient access in under two days with enhanced efficacy [177].
C-CAR088: Derived employing an scFv obtained from a human IgG1 antibody with high binding affinity (KD = 0.08 nM) for epitome cluster E3 of the BCMA extracellular domain [178].
CART- ddBCMA: A product of Arcelix that utilizes a non-scFv synthetic BCMA-binding domain, known as a D-Domain [179].
NXC-201 (HBI0101): Similar in structure to cilta-cel and ide-cel in that it incorporates the same 4-1BB and CD3z signaling entities [180,181], this BCMA-targeted product is currently under investigation for both RRMM and AL (amyloid light chain) amyloidosis (NCT04720313).
Table 8. Selected Trials of BCMA-Directed CAR T-Cell Products in Multiple Myeloma (MM).
Table 8. Selected Trials of BCMA-Directed CAR T-Cell Products in Multiple Myeloma (MM).
Trial ID (References) Drugs Phase Enrollment (N) Trial Title
NCT03361748 [169] Ide II 149 Multicenter Study to Determine the Efficacy and Safety of bb2121 in Subjects With RRMM (KarMMa)
NCT03601078 [182,183] Ide +/- Len II 235 Multi-cohort, Open-label, Multicenter Study to Evaluate the Efficacy and Safety of bb2121 in Subjects With RRMM and in Subjects With Clinical High-Risk MM (KarMMa-2)
NCT03651128 [170] Ide + SOC MM agents III 381 Multicenter, Randomized, Open-label Study to Compare the Efficacy and Safety of bb2121 Versus Standard Regimens in Subjects With RRMM (KarMMa-3)
NCT04855136 Ide + CC-220 vs. Ide + BMS-986405 I/II 312 Exploratory Trial to Determine Recommended Phase 2 Dose (RP2D), Safety and Preliminary Efficacy of bb2121 (Ide-cel) Combinations in Subjects With RRMM (KarMMa-7)
NCT03548207 [184,185,186] Cil I/II 126 Open-Label Study of JNJ-68284528, A Chimeric Antigen Receptor T-Cell (CAR-T) Therapy Directed Against BCMA in Subjects With RRMM (CARTITUDE-1)
NCT04133636 [187,188,189] Cil + Len + Dara + Dex + Bort II 169 Multicohort Open-Label Study of JNJ-68284528, a Chimeric Antigen Receptor T Cell (CAR-T) Therapy Directed Against BCMA in Subjects With MM (CARTITUDE-2)
NCT04181827 [173] Pom + Bort + Dex + Dara +/- Cil III 419 Randomized Study Comparing JNJ-68284528, a Chimeric Antigen Receptor T Cell (CAR-T) Therapy Directed Against BCMA, Versus Pomalidomide, Bortezomib and Dexamethasone (PVd) or Daratumumab, Pomalidomide and Dexamethasone (DPd) in Subjects With Relapsed and Lenalidomide-Refractory MM (CARTITUDE-4)
NCT04923893 [190] Bort + Dex + Len + Cil + Ctx + Flu III 650 Randomized Study Comparing Bortezomib, Lenalidomide and Dexamethasone (VRd) Followed by Ciltacabtagene Autoleucel, a Chimeric Antigen Receptor T Cell (CAR-T) Therapy Directed Against BCMA Versus Bortezomib, Lenalidomide, and Dexamethasone (VRd) Followed by Lenalidomide and Dexamethasone (Rd) Therapy in Participants With NDMM for Whom Hematopoietic Stem Cell Transplant is Not Planned as Initial Therapy (CARTITUDE-5)
NCT05257083 [191] Dara + Bort + Len + Dex +/- (Cil + Ctx + Flu) III 750 Randomized Study Comparing Daratumumab, Bortezomib, Lenalidomide and Dexamethasone (DVRd) Followed by Ciltacabtagene Autoleucel Versus Daratumumab, Bortezomib, Lenalidomide and Dexamethasone (DVRd) Followed by ASCT in Participants With NDMM Who Are Transplant Eligible (CARTITUDE-6)
NCT03758417 [192] Cil II 130 Open-Label Study of LCAR-B38M CAR-T Cells, a Chimeric Antigen Receptor T-cell (CAR-T) Therapy Directed Against BCMA in Chinese Subjects With RRMM (CARTIFAN-1)
NCT03090659 [193] Cil I/II 100 Study of Legend Biotech BCMA-chimeric Antigen Receptor Technology in Treating RRMM Patients (LEGEND-2)
NCT03975907 [175] Zev I/II 114 Open Label Trial to Evaluate the Safety and Efficacy of Fully Human Anti-BCMA Chimeric Antibody Receptor Autologous T Cell（CAR T）in Patients With RRMM (LUMMICAR STUDY 1)
NCT03915184 [194,195] Zev I/II 105 Open Label, Multi-center Trial to Evaluate the Safety and Efficacy of Autologous CAR BCMA T Cells (CT053) in Patients With RRMM (LUMMICAR STUDY 2)
NCT05066646 [174] CT103A I/II 132 Study on Fully Human BCMA Chimeric Antigen Receptor Autologous T Cell Injection (CT103A) in the Treatment of Patients With RRMM (FUMANBA-1)
NCT04318327 [196] PHE885 I 96 Open Label, Study of B-cell Maturation Antigen (BCMA)-Directed CAR-T Cells in Adult Patients With MM
NCT05172596 PHE885 II 136 Study of PHE885, B-cell Maturation Antigen (BCMA)- Directed CAR-T Cells in Adult Participants With RRMM.
NCT05521802 C-CAR088 I/II 92 Study of CBM.BCMA Chimeric Antigen Receptor T Cell Product (C-CAR088) for Treating Patients With RRMM
NCT04295018 [178] C-CAR088 I 10 A Study Evaluating Safety and Efficacy of C-CAR088 Treatment in Subjects With RRMM
NCT05396885 [197] CART- ddBCMA II 110 Study of CART-ddBCMA for the Treatment of Patients With RRMM (IMMagine-1)
NCT04394650 [198] CC-98633/BMS-986354 I 150 Multi Center, Open Label Study of CC-98633, BCMA Targeted NEX-T Chimeric Antigen Receptor (CAR) T Cells, in Subjects With RRMM
NCT04720313 [180] NXC-201 I 160 Dose Escalation and Safety Study of NXC-201 (Formerly HBI0101) CART in BCMA-Expressing MM Patients and AL Amyloidosis
AL = amyloid light chain; Bort = bortezomib; Cil = ciltacabtagene autoleucel; Ctx = cyclophosphamide; Dara = daratumumab; Dex = dexamethasone; Flu = fludarabine; Ide = idecabtagene vicleucel; Len = lenalidomide; MM = multiple myeloma; NDMM = newly diagnosed multiple myeloma; Pom = pomalidomide; RRMM = relapsed and/or refractory multiple myeloma; SOC = standard of care; Zev = zevorcabtagene autoleucel.
While impressive results in terms of depth and duration of response have been obtained in many cases with BCMA-directed T-cell therapies, relapse is a frequent occurrence. A potential limitation of BCMA-targeted immunotherapy is the heterogeneous nature of the antigen’s expression on myeloma cells, as well as its reduction or complete loss during drug exposure. GC012F, which targets both BCMA and CD19 is an attempt to circumvent this issue. This dual-targeting autologous product, which is currently the subject of six different RRMM trials, can be manufactured in 36 hours or less using the FasTCAR platform, according to its innovator Gracell [199,200]. In one such trial (NCT04236011/ NCT04182581) MRD negativity was reported to occur in 21/28 RRMM patients after 28 days of a single infusion [201]. A study of the drug included as a component of standard therapy in 13 transplant-eligible high risk NDMM patients (NCT04935580) attained 100% for both ORR and MRD negativity after a median of 5.3 months [200].
As seen with BiTE therapy, GPRC5D also has begun to play a major role in the development of new CAR T-cell targeted therapeutics for RRMM [202]. One of the most promising of the GPRC5D-targeted agents is MCARH109, the subject of an ongoing phase I trial (NCT04555551). An ORR of 71% (10/17) was reported for the entire cohort in this study. While the drug was well-tolerated generally, a single patient did experience both Grade 4 CRS and ICANS [203]. Another entry in the anti-GPRC5D CAR T-cell arena is BMS-986393 (CC-95266) currently the focus of a phase I dose-escalation study (NCT04674813). An initial report of evaluable patients found an ORR of 86% (12/14) after one-month of therapy. Significantly, eight of the patients displayed high-risk cytogenetics - del[17p], t[4;14], and/or t[14;16] [204]. NCT05016778 is yet another phase I study evaluating a GPRC5D-directed CAR T-cell preparation, named OriCAR-017. Data from this trial, titled POLARIS, reported a 100% response rate on the first 10 patients evaluated [205]. Finally, CAR T-cells targeting SLAMF7 (NCT03958656 and NCT03710421) and CD38 (NCT03464916) have received some attention based on preclinical studies but have resulted in no published patient data.
Alternatives to T-cells also have been under consideration in efforts to expand available options in the CAR arena for RRMM, the primary candidates being autologous anti-BCMA engineered NK cells [206]. An examination of the NCI clinical trials data base uncovered two such studies (NCT03940833 and NCT05008536) although neither has yielded published data thus far.
Even though autologously administered CAR T-cells have thus far produced highly promising results, their use is not without drawbacks, such as the short durations of response they elicit, the extended time and complexity involved in their manufacture, as well as the high risk of CRS and other dose-limiting adverse events. Consequently, some CAR T-cell originators have pioneered programs to develop “off-the shelf” allogeneic anti-BCMA products that employ T-cells from healthy donors. Although efficacy and toxicity data have been sparse so far, the potential feasibility of this approach to RRMM therapy continues to undergo intense scrutiny with the current pipeline of agents in this category being headed by three major players: ALLO-715 from Allogene Therapeutics, Precision Bioscience’s PBCAR269A, and Caribou Bioscience’s CB-011.
ALLO-715 is a product of the proprietary Transcription Activator-like Effector Nuclease (TALEN®) system, a site-specific BCMA gene-editing technique that is hypothesized to limit T-cell receptor-mediated immune reactions, including rapid rejection and graft versus host disease (GvHD) [207]. Data from the phase I UNIVERSAL trial (NCT04093596) recently reported an ORR of 55.8% (24/43) in patients who received ALLO-715 following lymphodepletion that included the anti-CD52 antibody ALLO- 647 in addition to cyclophosphamide/fludarabine [208]. It is noteworthy that the design strategy of ALLO-715 also incorporates an off-switch, a CD20-based mimotope capable of inactivation by rituximab. The Arcus gene-editing platform, which is based on the proprietary homing endonuclease I-Crel scaffold [209], serves as the foundation for production of PBCAR269A. This allogeneic product currently is under study in a phase I/II trial (NCT04171843) that also includes the gamma-secretase inhibitor nirogacestat. As yet, there has been no published patient data concerning this study. The CRISPR-edited production of CB-011 recently was outlined by Berdeja et al. [210], who also described the methodology used in the ongoing clinical evaluation of this agent (NCT05722418; CaMMouflage). Two additional BCMA-directed allogeneic CAR candidates now under investigation for RRMM but with no reported results are Allogene’s ALLO-605 (NCT05000450) [211] and Poseidon’s P-BCMA-ALLO1 (NCT04960579) [212]. Significantly, the latter product is marked by inclusion in its design of a truncated caspase 9 domain as a safety switch that can activate apoptosis upon administration of the caspase 9 dimerizing agent rimiducid if patient safety is threatened [213]. It should be noted that construction of P-BCMA-ALLO1 was informed by the promising initial results [214] obtained with the company’s autologous entry into the field, P-BCMA-101, which has since been superseded in development by the allogeneic product [215]. Finally, the potential of a few other allogeneic CAR products that are in early stage development for RRMM have been described; these include the SLAMF7/CS1-directed UCARTCS1 (NCT04142619; MELANI-01) [216], a dual targeting BCMA/GPRC5D NK cell preparation [217], and FT538, a multiplex engineered NK product derived from induced pluripotent stem cells (NCT04614636) [218].
Table 9 summarizes both efficacy and toxicity data as found in ten different meta-analytic studies of BCMA-targeted CAR T-cell trials and indicates the high degree of effectiveness and safety of the various autologous products described above. In the years ahead similar studies comparing the autologous products with the now-emerging allogeneic preparations will help illuminate the path forward concerning the role of ACT in the treatment of RRMM.

7. Cytokine Release Syndrome and Neurotoxicity

The potential to produce severe life-threatening toxicity, often divided into two general types, is a major challenge confronting the use of immunotherapeutic measures in the treatment of MM and other hematologic cancers. The first type results from T-cell recognition and activation against the targeted malignant cells followed by uncontrolled release of high levels of cytokines at high levels (on-target, on-tumor toxicity). In the second case the released cytokines bind to the target antigen located on normal cells (on-target, off-tumor toxicity). A low risk of on-target, off-tumor toxicity attends the use of the anti-myeloma BCMA-targeted agents described in this review since distribution of the target antigen is confined virtually to plasma cells. On the other hand, on-tumor, on-target toxicities can be very serious since they often are not easily reversed and may require intensive multidisciplinary care. The discussion that follows concerns the on-target, on-tumor types of adverse reactions.
The most important adverse effects that accompany CAR T-cell therapy are the cytokine release syndrome (cytokine storm; CRS) and neurotoxicity, both of which are observed in varying degrees of severity in a percentage of participants in every trial involving CAR T-cell products. The neurotoxic reactions are often referenced in the literature by either of two synonymous terms: CAR T-cell-related encephalopathy syndrome (CRES) or immune effector cell–associated neurotoxicity syndrome (ICANS).
Generally occurring within the first two weeks of therapy and often resembling a severe inflammatory reaction, the symptoms of CRS are attributed to marked increased expression and release of certain cytokines, including IL-6, IL-2R, IL-10, IFN-g, and TNF-α [229]. Gradation of CRS symptoms is based on a 1-4 system with Grade 4 having severe life-threatening consequences [230]. Moreover, CRS has been implicated as a major contributor to the deadly effects accompanying COVID-19 infections [231]. The IL-6 blocker tocilizumab (Actemra®), an IL-6 blocker often given with corticosteroids, is the treatment of choice for cases of CRS associated with CAR T-cell therapy. FDA approval of tocilizumab for this indication was granted in 2017 [232]. However, the efficacy of combining corticosteroids with tocilizumab in the management of CRS has not been investigated through randomized controlled studies. A recent metanalysis of 53 studies involving a total of 2092 RRMM patients comparing BCMA-targeting bispecific antibody with CAR T-cell therapies showed that the latter are associated with higher rates and longer durations of Grade >3 CRS and more frequent use of tocilizumab/corticosteroid [233].
In order to help mitigate toxicity arising from CAR T-cell therapy some products have incorporated a safety switch to enable activity to be curtailed by pharmacological means [234,235]. One early example is the inclusion within the construct of a CD20 receptor that can be turned “off” by administration of the CD20 blocker rituximab [236]. The incorporation of a non-functional truncated epidermal growth factor receptor (tEGFR) inhibitable by cetuximab represents another illustration [237]. Dimerization of caspase-9 by rimiducid to activate apoptosis is yet another example [238]. The various types of molecular safety switches employed in CAR T-cell design, including the strengths and weaknesses of each, have been discussed in a recent review [239].

8. Checkpoint Inhibitors

Immune checkpoint blockade has emerged as a major approach to anticancer drug development over the past decade. The strategy has as its foundation the interaction of specific cell surface biomarkers and their cognate ligands which enable malignant cells to evade immune surveillance and elimination. The development of mAbs to block these biomarker/ligand interactions remains a major focus of cancer immunotherapy with the bulk of attention focused on two T-cell surface proteins: CTLA-4 (cytotoxic T-lymphocyte–associated protein-4) and the programmed death (PD) receptor and their corresponding ligands, referred to as B7-1/B7-2 and PD-L1 respectively, on targeted tumor cells. These receptor/ligand pairs have been employed successfully as targets for a number of different cancers including non-small cell lung cancer, renal cell carcinoma, melanomas, and Hodgkin’s lymphoma [240]; however, their utility as targets in leukemias and MM has yet to be conclusively demonstrated [241]. A myeloma-based trial (NCT02681302) of the anti-CTLA-4 mAb ipilimumab combined with another checkpoint inhibitor, nivolumab, is currently ongoing. An initial report from this study concluded that the combined checkpoint inhibitor therapy is safe and has potential to increase the “depth of response in patients with high-risk disease” [242]. In a major development two phase III studies (NCT02576977 KEYNOTE 183 and NCT02579863 KEYNOTE 185) [243,244] of the PD-1 blocker pembrolizumab combined with immunomodulators in MM had to be terminated when decreased OS was found in both trials [245]. Although the mechanism underlying this safety concern remains unknown, several trials of pembrolizumab either as sole therapy or in combination with established anti-myeloma agents remain in effect (see Table 10).
Also under clinical study for MM are the PD-1 blockers nivolumab and cemiplimab and the PD-L1 inhibitor atezolizumab. A trial (NCT01592370) that incorporated a total of 81 hematologic cancer patients found that the RRMM (N = 27) cohort received negligible clinical benefit. (PFS = 10 weeks; ORR = 4%) [246] from nivolumab monotherapy. Another study (NCT02681302) of 7 high-risk transplant-naïve MM patients receiving combined checkpoint inhibitor therapy (ipilimumab + nivolumab) reported OS and PFS rates of 40% and 57.1% after 18 months [242]. In another instance, data acquired before the trial (NCT03312530) was terminated early demonstrated that atezolizumab provided some minor benefit when combined with the MEK inhibitor cobimetinib and the BCl2 blocker venetoclax in RRMM patients [247]. Likewise, only marginal benefits were realized in a trial in which isatuximab and cemiplimab were employed (NCT03194867) as treatment in 106 RRMM subjects [248].
Like T cells, macrophages, members of the innate immune system, are also known to express a checkpoint receptor known as signal regulatory protein a (SIRPa or CD172a), which attaches to its ligand CD47, a transmembrane protein overexpressed by cancer cells, including myeloma cells. When SIRPa and CD47 interact, a signaling cascade is initiated leading to suppression of macrophage phagocytic activity, sometimes known as the “don’t eat me” signal [249]. Recently, efforts have emerged to target this immune checkpoint in the search for novel approaches to treat MM [250]. One of these, the CD47 blocker magrolimab, is the subject of a current trial (NCT04892446) in combination with various established anti-myeloma agents [251]. Clinical investigations also have begun on two additional anti-CD47 mAbs: AO-176 (NCT04445701) [252] and TTI-622 (NCT05139225) (see Table 10). However, no data have yet appeared to substantiate the clinical validity of the CD47-targeted approach to MM.
Table 10. Selected Current Trials of Checkpoint Inhibitors in MM.
Table 10. Selected Current Trials of Checkpoint Inhibitors in MM.
PD-1 Inhibitors
Trial ID (References) Drugs Phase Enrollment (N) Trial Title
NCT05204160 Pembro II 30 Study of Pembrolizumab as Salvage Therapy Among MM Patients Progressing on CAR-T Cell Therapy
NCT05191472 [253] Pembro II 25 Study of Pembrolizumab in MM Patients Relapsing After or Refractory to Anti-BCMA CAR-T Therapies
NCT02636010 Pembro II 20 Multicenter, Open Label, Clinical Trial of Pembrolizumab as Consolidation Therapy in MM Patients With Residual Disease After Treatment
NCT03267888 Pembro I 26 Pilot Study of Pembrolizumab and Single-Fraction, Low-Dose, Radiation Therapy in Patients With RRMM
NCT02331368 Pembro II 32 Multi-center Study of Anti-Programmed-Death-1 During Lymphopenic State After High-Dose Chemotherapy and ASCT for MM
NCT05514990 Pembro + Bort + Dex +/- Pelareorep I/II 42 Study of Standard Doses of Bortezomib and Pembrolizumab ± Reovirus (Pelareorep) Combination Therapy in Patients With RRMM (AMBUSH Study)
NCT02906332 [254] Pembro + Len + Dex II 16 Trial of Pembrolizumab + Lenalidomide + Dexamethasone as Post-ASCT Consolidation in Patients With High-risk MM
NCT03848845 [60] Pembro + BelMaf I/II 41 Single Arm Open-Label Study to Explore Safety and Clinical Activity of GSK2857916 Administered in Combination With Pembrolizumab in Subjects With RRMM (DREAMM 4)
NCT02880228 Pembro + Len + Dex II 11 Trial of Pembrolizumab, Lenalidomide, and Dexamethasone for Initial Therapy of NDMM Eligible for ASCT
NCT03506360 Pembro + Ixaz + Dex II 13 Trial of Pembrolizumab, Ixazomib, and Dexamethasone for RRMM
NCT03194867 [248] Isa +/- Cem I/II 106 Study to Evaluate Safety, Pharmacokinetics and Efficacy of Isatuximab in Combination With Cemiplimab in Patients With RRMM
NCT03184194 Niv + Dara +/- Ctx II 62 Study of Nivolumab Combined With Daratumumab With or Without Low-dose Cyclophosphamide in RRMM
NCT03605719 Niv + Carf + Dex +/- Pelareorep I 23 Dexamethasone, Carfilzomib, and Nivolumab With Pelareorep for RRMM
NCT04119336 Niv + Ixaz + Ctx + Dex II 50 Study of Nivolumab in Combination With Ixazomib, Cyclophosphamide, and Dexamethasone in RRMM
NCT02726581 Pom + Dex +/- Niv III 170 Open-Label, Randomized Trial of Combinations of Nivolumab, Pomalidomide and Dexamethasone in RRMM
NCT02681302 [242]a Niv + Ipil I/II 35 Study of Combined Check Point Inhibition After ASCT in Patients at High Risk for Post-transplant Recurrence
NCT02612779 (Niv + Elo) vs. (Niv + Elo + Pom + Dex) II 74 Study of Elotuzumab in Combination With Pomalidomide and Low Dose Dexamethasone and Elotuzumab in Combination With Nivolumab in Patients With RRMM to Prior Treatment With Lenalidomide.
NCT03292263 Mel + Niv I/II 30 ASCT With Nivolumab in Patients With MM
NCT01592370 [246] Niv vs. (Niv + Ipil) vs. (Niv + Liri) vs. (Niv + Dara + Pom) + Dex) vs. (Niv + Dara) I/Ii 316 An Investigational Immuno-Therapy Study to Determine the Safety and Effectiveness of Nivolumab and Daratumumab in Patients With MM
PD-L1 Inhibitors
NCT03312530 [247] (Cobi + Atez) vs. (Cobi + Ven +/- Atez) I/II 49 Study of Cobimetinib Administered as Single Agent and in Combination With Venetoclax, With or Without Atezolizumab, in Patients With RRMM
NCT02431208 [255] (Atez + Len) vs. (Atez + Dara) vs. (Atez + Dara + Len) vs. (Atez + Dara + Pom) vs. (Dara + Pom + Dex) I 85 Study of the Safety and Pharmacokinetics of Atezolizumab Alone or in Combination With an Immunomodulatory Drug and/or Daratumumab in Patients With RRMM and ASCT
CD47 Inhibitors
NCT04892446 [251,256] (Mag + Dara) vs. (Mag + Pom + Dex) vs. (Mag + Carf + Dex) vs. (Mag + Bort + Dex) II 153 Multi-Arm Study of Magrolimab Combinations in Patients With RRMM
NCT04445701 [252] AO-176 vs. (AO-176 + Dex +/- Bort) I/II 157 Dose Escalation Safety and Tolerability Study of AO-176 as Monotherapy and in Combination With Bortezomib and Dexamethasone in Adults With RRMM
NCT05139225 TTI-622 + Dara-Hyal I 32 Study Of The Combination Of CD47 Blockade With SIRP-Alpha FC Fusion Proteins (TTI-622) And Daratumumab Hyaluronidase-fihj For Patients With RRMM
ASCT = autologous stem cell transplantation; Atez = atezolizumab; BelMaf = belantamab mafodotin; Bort = bortezomib; Cem = cemiplimab; Carf = carfilzomib; Cobi = cobimetinib; Ctx = cyclophosphamide; Dara = daratumumab; Dex = dexamethasone. Elo = elotuzumab; Hyal = hyaluronidase; Ipil = ipilimumab; Isa = isatuximab; Ixaz = ixazomib; Len = lenalidomide; Mag = magrolimab; Mel = melphalan; MM = multiple myeloma; NDMM = newly diagnosed multiple myeloma; Niv = nivolumab; Pembro = pembrolizumab; Pom = pomalidomide; RRMM = relapsed and/or refractory multiple myeloma; Ven = venetoclax. a study includes patients with lymphomas and high-risk recurrent MM.

9. Summary and Conclusions

The therapeutic measures used to treat MM have undergone a fundamental shift since the beginning of the current century with the introduction of several entirely new classes of agents, such as proteasome inhibitors, immunomodulators, nuclear export blockers, and apoptosis inducers. These advances are reflected in the dramatic improvements in the 5-year survival rates for the disease, which had risen gradually from 25% in the 1975-77 period to 32% for 1995-97 but climbed sharply to 58% during 2012-2018 as the impact of these newer modalities began to come into play [2]. The benefits of these therapeutic advances are further evidenced by such measures as accumulated PFS, OS, and ORR data and quality of life studies [257,258]. The definition of MM itself has changed over the years, moving away from the traditional CRAB model toward a risk stratification approach that includes factors that may be determinant before signs and symptoms of the disease emerge, such as the progression from MGUS to MM. These criteria which include bone marrow studies and imaging technologies, as well as free light chain, immunoglobulin, and cytogenetic analyses, have been woven into the fabric of contemporary diagnostic procedures, projection of disease course, and evaluation of the expanding number of available intervention strategies tailored to the individual patient [6].
The 2015 FDA approval of daratumumab heralded the advent of the era of immunologic-based approaches to MM as this monoclonal antibody quickly rose to a position of prominence as a core component in the treatment of MM, whether newly diagnosed or at the relapsed/refractory stage. Since that seminal event the immunologic tools available in the clinic to treat MM has greatly expanded to include additional mAbs, such as isatuximab, bispecifics, and CAR-T products. However, this sense of optimism is balanced by the reality that MM still is considered incurable regardless of the therapeutic measures employed. Initial therapeutic benefits are all too frequently followed by refractoriness to treatment and resulting relapse.
The identification of suitable tumor-driving biomarkers for the disease that can serve as potential therapeutic targets is fundamental to immunotherapeutic approaches to MM. Currently, the surface molecule in the vanguard of this pursuit is BCMA, which accounts for most of the immunologically based clinical trials currently in progress. While several studies of BCMA-targeted CAR T-cell therapies have been shown to provide ORRs of at least 80%, the response durations tend to be short. Moreover, BCMA expression by myeloma cells may not be as homogeneous as previously believed. For example, in one study a substantial proportion (33/85) of MM patients was found to be BCMA-negative [259]. In addition, downregulated BCMA expression by tumor cells has been reported during CAR T-cell therapy, as well as instances in which a significant fraction of initially responding patients experienced relapse despite continued expression of BCMA [260,261,262,263]. Also relevant to the discussion is a genome-wide gene-editing CRISPR study that failed to identify BCMA as being included among 90 different genes essential for MM [264]. As a consequence, there is increasing interest in combinatorial immunologically based strategies that employ BCMA with other validated myeloma targets, such as CD38, SLAMF7, and CD19 [265] or with emerging viable targets like GPRC5D [217,266]. Indeed, GPRC5D has special appeal as a target in immunotherapy constructs since its expression is linked with poor prognosis in MM [134] and, unlike BCMA, does not shed from the cell surface. In addition, GPRC5D expression is independent of BCMA, suggesting that it may serve as an alternative target in cases of anti-BCMA therapy relapse [267]. The recent approval of the GPRC5D x CD3 bispecific talquetamab for MM is a promising sign in this regard that portends the possibility of potentially fruitful avenues for discovery of innovative approaches to treat RRMM based on this biomarker.
The development of new and ground-breaking therapies to treat RRMM also will depend on gaining much better insight into the mechanisms that drive resistance to treatment, especially the role played by the bone marrow microenvironment and the factors that enable malignant plasma cells to escape immune surveillance. Advances in understanding these basic mechanisms will translate into improved outcomes, including the ability to prevent bone loss [268].
In addition to ORR, CR, OS, PFS, and other assessments, the ability to detect minimal residual disease (MRD), i.e., complete absence of any detectable clonal plasma cells, has emerged as a key factor in directing anti-myeloma therapies enabled by technologic advances. Attainment of MRD negativity is increasingly seen as a reliable marker and strategic objective in both clinical trials and in the monitoring of individual patients receiving standard care [269].
In conclusion, it is most encouraging to note that the five-year survival rate for MM is now approaching 60%, based on data that only begins to capture outcomes from the present era in which monoclonal antibodies, such as daratumumab, have assumed a much greater therapeutic role in the disease. The vast expansion over the past two decades in understanding the mechanisms that underlie MM initiation, proliferation, survival, and metastasis along with the identification of druggable biomarkers that have led to increasingly efficacious therapies has elevated the disease to its current status as a manageable, albeit still incurable, chronic condition. Nevertheless, the field continues to be burdened with challenges of relapse as patients become refractory to treatment and eventually succumb to the disease. Moving forward, confronting these challenges will need to continue with sustained and vigorous resolve in order for the goal of a true cure to become a future reality.

References

  1. van de Donk, N.; Pawlyn, C.; Yong, K.L. Multiple myeloma. Lancet 2021, 397, 410–427. [Google Scholar] [CrossRef] [PubMed]
  2. Siegel, R.L.; Miller, K.D.; Wagle, N.S.; Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin. 2023, 73, 17–48. [Google Scholar] [CrossRef] [PubMed]
  3. Padala, S.A.; Barsouk, A.; Barsouk, A.; Rawla, P.; Vakiti, A.; Kolhe, R.; Kota, V.; Ajebo, G.H. Epidemiology, staging, and management of multiple myeloma. Med Sci (Basel) 2021, 9, 3. [Google Scholar] [CrossRef] [PubMed]
  4. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
  5. Giaquinto, A.N.; Miller, K.D.; Tossas, K.Y.; Winn, R.A.; Jemal, A.; Siegel, R.L. Cancer statistics for African American/Black People 2022. CA Cancer J. Clin. 2022, 72, 202–229. [Google Scholar] [CrossRef] [PubMed]
  6. Callander, N.S.; Baljevic, M.; Adekola, K.; Anderson, L.D.; Campagnaro, E.; Castillo, J.J.; Costello, C.; Devarakonda, S.; Elsedawy, N.; Faiman, M.; et al. NCCN Guidelines® Insights: Multiple myeloma, version 3.2022. J. Natl. Compr. Canc. Netw. 2022, 20, 8–19. [Google Scholar] [CrossRef]
  7. Marcon, C.; Simeon, V.; Deias, P.; Facchin, G.; Corso, A.; Derudas, D.; Montefusco, V.; Offidani, M.; Petrucci, M.T.; Zambello, R.; et al. Experts' consensus on the definition and management of high risk multiple myeloma. Front. Oncol. 2022, 12, 1096852. [Google Scholar] [CrossRef]
  8. Landgren, O.; Kyle, R.A.; Pfeiffer, R.M.; Katzmann, J.A.; Caporaso, N.E.; Hayes, R.B.; Dispenzieri, A.; Kumar, S.; Clark, R.J.; Baris, D.; et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: A prospective study. Blood 2009, 113, 5412–5417. [Google Scholar] [CrossRef]
  9. Kyle, R.A.; Larson, D.R.; Therneau, T.M.; Dispenzieri, A.; Kumar, S.; Cerhan, J.R.; Rajkumar, S.V. Long-term follow-up of monoclonal gammopathy of undetermined significance. N. Engl. J. Med. 2018, 378, 241–249. [Google Scholar] [CrossRef]
  10. Yavorkovsky, L.L. Smoldering multiple myeloma 40 years later: A story of unintended disease. Expert Rev. Hematol. 2021, 14, 149–153. [Google Scholar] [CrossRef]
  11. Liu, C.; Yang, M.; Zhang, D.; Chen, M.; Zhu, D. Clinical cancer immunotherapy: Current progress and prospects. Front. Immunol. 2022, 13, 961805. [Google Scholar] [CrossRef] [PubMed]
  12. Anagnostou, V.; Landon, B.V.; Medina, J.E.; Forde, P.; Velculescu, V.E. Translating the evolving molecular landscape of tumors to biomarkers of response for cancer immunotherapy. Sci. Transl. Med. 2022, 14, eabo3958. [Google Scholar] [CrossRef] [PubMed]
  13. Leleu, X.; Martin, T.; Weisel, K.; Schjesvold, F.; Iida, S.; Malavasi, F.; Manier, S.; Chang-Ki, M.; Ocio, E.M.; Pawlyn, C.; et al. Anti-CD38 antibody therapy for patients with relapsed/refractory multiple myeloma: Differential mechanisms of action and recent clinical trial outcomes. Ann. Hematol. 2022, 101, 2123–2137. [Google Scholar] [CrossRef] [PubMed]
  14. Minakata, D.; Fujiwara, S.I.; Yokoyama, D.; Noguchi, A.; Aoe, S.; Oyama, T.; Koyama, S.; Murahashi, R.; Nakashima, H.; Hyodo, K.; et al. Relapsed and refractory multiple myeloma: A systematic review and network meta-analysis of the efficacy of novel therapies. Br. J. Haematol. 2023, 200, 694–703. [Google Scholar] [CrossRef]
  15. Tauseef, A.; Zafar, M.; Silberstein, P.; Nahas, J.; Frederickson, T.; Abodunrin, F.; Abbas, A.; Arshad, W.; Lateef, N.; Rangoonwala, H.; et al. Role of daratumumab in relapsed or refractory multiple myeloma patient: A meta-analysis and literature to review. J Family Med Prim Care 2022, 11, 2648–2655. [Google Scholar] [CrossRef]
  16. Jakubowiak, A.J.; Kumar, S.; Medhekar, R.; Pei, H.; Lefebvre, P.; Kaila, S.; He, J.; Lafeuille, M.H.; Cortoos, A.; Londhe, A.; et al. Daratumumab improves depth of response and progression-free survival in transplant-ineligible, high-risk, newly diagnosed multiple myeloma. Oncologist 2022, 27, e589–e596. [Google Scholar] [CrossRef]
  17. Botta, C.; Gigliotta, E.; Paiva, B.; Anselmo, R.; Santoro, M.; Otero, P.R.; Carlisi, M.; Conticello, C.; Romano, A.; Solimando, A.G.; et al. Network meta-analysis of randomized trials in multiple myeloma: Efficacy and safety in frontline therapy for patients not eligible for transplant. Hematol. Oncol. 2022, 40, 987–998. [Google Scholar] [CrossRef]
  18. Aiman, W.; Anwar, A.; Satti, D.I.; Hamza, M.; Perez, A.M.; Khan, A.A.; Nepal, A.; Supraja, A.; Yeesau, M.; Nanjundaiah, N.; et al. Addition of daratumumab to drug regimens in the treatment of multiple myeloma: A systematic review and meta-analysis of randomized clinical trials. Clin. Lymphoma Myeloma Leuk. 2022, 22 Suppl 2, S405. [Google Scholar] [CrossRef]
  19. Mateos, M.V.; Rigaudeau, S.; Basu, S.; Spicka, I.; Schots, R.; Wrobel, T.; Cook, G.; Beksac, M.; Gries, K.S.; Kudva, A.; et al. Switching to daratumumab SC from IV is safe and preferred by patients with multiple myeloma. J. Oncol. Pharm. Pract. 2022, 29, 1172–1177. [Google Scholar] [CrossRef]
  20. Nooka, A.K.; Gleason, C.; Sargeant, M.O.; Walker, M.; Watson, M.; Panjic, E.H.; Lonial, S. Managing infusion reactions to new monoclonal antibodies in multiple myeloma: Daratumumab and elotuzumab. J. Oncol. Pract. 2018, 14, 414–422. [Google Scholar] [CrossRef]
  21. Chapuy, C.I.; Nicholson, R.T.; Aguad, M.D.; Chapuy, B.; Laubach, J.P.; Richardson, P.G.; Doshi, P.; Kaufman, R.M. Resolving the daratumumab interference with blood compatibility testing. Transfusion (Paris) 2015, 55, 1545–1554. [Google Scholar] [CrossRef] [PubMed]
  22. Deckert, J.; Wetzel, M.C.; Bartle, L.M.; Skaletskaya, A.; Goldmacher, V.S.; Vallee, F.; Zhou-Liu, Q.; Ferrari, P.; Pouzieux, S.; Lahoute, C.; et al. SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent antitumor activity in models of multiple myeloma and other CD38+ hematologic malignancies. Clin. Cancer Res. 2014, 20, 4574–4583. [Google Scholar] [CrossRef] [PubMed]
  23. Dhillon, S. Isatuximab: First approval. Drugs 2020, 80, 905–912. [Google Scholar] [CrossRef]
  24. Attal, M.; Richardson, P.G.; Rajkumar, S.V.; San-Miguel, J.; Beksac, M.; Spicka, I.; Leleu, X.; Schjesvold, F.; Moreau, P.; Dimopoulos, M.A.; et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): A randomised, multicentre, open-label, phase 3 study. Lancet 2019, 394, 2096–2107. [Google Scholar] [CrossRef]
  25. Moreau, P.; Dimopoulos, M.A.; Mikhael, J.; Yong, K.; Capra, M.; Facon, T.; Hajek, R.; Špička, I.; Baker, R.; Kim, K.; et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): A multicentre, open-label, randomised phase 3 trial. Lancet 2021, 397, 2361–2371. [Google Scholar] [CrossRef]
  26. Martin, T.; Dimopoulos, M.A.; Mikhael, J.; Yong, K.; Capra, M.; Facon, T.; Hajek, R.; Špička, I.; Baker, R.; Kim, K.; et al. Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: Updated results from IKEMA, a randomized phase 3 study. Blood cancer journal 2023, 13, 72. [Google Scholar] [CrossRef]
  27. Quach, H.; Parmar, G.; Ocio, E.; Prince, H.M.; Oriol, A.; Tsukada, N.; Sunami, K.; Bories, P.; Karanes, C.; Madan, S.; et al. Subcutaneous isatuximab administration by an on-body delivery system in combination with pomalidomide-dexamethasone in relapsed/refractory multiple myeloma patients: Interim phase 1b study results. Clinical Lymphoma Myeloma & Leukemia 2022, 22, S184–S185. [Google Scholar]
  28. Quach, H.; Parmar, G.; Ocio, E.M.; Prince, H.M.; Oriol, A.; Tsukada, N.; Sunami, K.; Bories, P.; Madan, S.; Semiond, D.; et al. Subcutaneous isatuximab administration by an on-body delivery system (OBDS) in combination with pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma: Phase 1b expansion study results. Blood 2022, 140 (Suppl. S1), 4412–4414. [Google Scholar] [CrossRef]
  29. Quach, H.; Parmar, G.; Ocio, E.; Prince, H.M.; Rocafiguera, A.O.; Tsukada, N.; Sunami, K.; Bories, P.; Karanes, C.; Madan, S.; et al. Subcutaneous (SC) isatuximab administration by an on-body delivery system (OBDS) in combination with pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM): Interim phase 1b study results. J. Clin. Oncol. 2022, 40, 8025. [Google Scholar] [CrossRef]
  30. Ishida, T. Therapeutic antibodies for multiple myeloma. Jpn. J. Clin. Oncol. 2018, 48, 957–963. [Google Scholar] [CrossRef]
  31. Lonial, S.; Dimopoulos, M.; Palumbo, A.; White, D.; Grosicki, S.; Spicka, I.; Walter-Croneck, A.; Moreau, P.; Mateos, M.V.; Magen, H.; et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N. Engl. J. Med. 2015, 373, 621–631. [Google Scholar] [CrossRef]
  32. Bruzzese, A.; Derudas, D.; Galli, M.; Martino, E.A.; Rocco, S.; Conticello, C.; Califano, C.; Giuliani, N.; Mangiacavalli, S.; Farina, G.; et al. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: Extended 3-year follow-up of a multicenter, retrospective clinical experience with 319 cases outside of controlled clinical trials. Hematol. Oncol. 2022, 40, 704–715. [Google Scholar] [CrossRef] [PubMed]
  33. Dimopoulos, M.A.; Lonial, S.; White, D.; Moreau, P.; Weisel, K.; San-Miguel, J.; Shpilberg, O.; Grosicki, S.; Špička, I.; Walter-Croneck, A.; et al. Elotuzumab, lenalidomide, and dexamethasone in RRMM: Final overall survival results from the phase 3 randomized ELOQUENT-2 study. Blood cancer journal 2020, 10, 91. [Google Scholar] [CrossRef] [PubMed]
  34. Gavriatopoulou, M.; Terpos, E.; Dimopoulos, M.A. The extended 4-year follow-up results of the ELOQUENT-2 trial. Oncotarget 2019, 10, 82–83. [Google Scholar] [CrossRef]
  35. Dimopoulos, M.A.; Dytfeld, D.; Grosicki, S.; Moreau, P.; Takezako, N.; Hori, M.; Leleu, X.; LeBlanc, R.; Suzuki, K.; Raab, M.S.; et al. Elotuzumab plus pomalidomide and dexamethasone for relapsed/refractory multiple myeloma: Final overall survival analysis from the randomized phase II ELOQUENT-3 trial. J. Clin. Oncol. 2023, 41, 568–578. [Google Scholar] [CrossRef] [PubMed]
  36. Jakubowiak, A.; Offidani, M.; Pegourie, B.; De La Rubia, J.; Garderet, L.; Laribi, K.; Bosi, A.; Marasca, R.; Laubach, J.; Mohrbacher, A.; et al. Randomized phase 2 study: Elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood 2016, 127, 2833–2840. [Google Scholar] [CrossRef]
  37. Silvennoinen, R.H.; Nahi, H.; Anttila, P.; Koskenvesa, P.; Lievonen, J.; Marttila, A.; Varmavuo, V.; Sikio, A.; Nurmi, M.; Saily, M.; et al. Carfilzomib, elotuzumab and dexamethasone for relapsed or refractory myeloma patients. Blood 2020, 136 (Suppl. S1), 20. [Google Scholar] [CrossRef]
  38. Shimura, Y.; Tsukamoto, T.; Yamaguchi, J.; Kuwahara-Ota, S.; Isa, R.; Nishiyama, D.; Kobayashi, T.; Horiike, S.; Suzuki, A.; Kuroda, J. Toward further simplification of elotuzumab therapy by subcutaneous administration. Int. J. Hematol. 2020, 112, 427–428. [Google Scholar] [CrossRef]
  39. Yu, J.; Song, Y.; Tian, W. How to select IgG subclasses in developing anti-tumor therapeutic antibodies. J. Hematol. Oncol. 2020, 13, 45. [Google Scholar] [CrossRef]
  40. Pereira, N.A.; Chan, K.F.; Lin, P.C.; Song, Z. The "less-is-more" in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity. mAbs 2018, 10, 693–711. [Google Scholar] [CrossRef]
  41. Sheyi, R.; de la Torre, B.G.; Albericio, F. Linkers: An assurance for controlled delivery of antibody-drug conjugate. Pharmaceutics 2022, 14, 396. [Google Scholar] [CrossRef]
  42. Jain, N.; Smith, S.W.; Ghone, S.; Tomczuk, B. Current ADC linker chemistry. Pharm. Res. 2015, 32, 3526–3540. [Google Scholar] [CrossRef] [PubMed]
  43. Fang, Y.; Hou, J. Immunotherapeutic strategies targeting B cell maturation antigen in multiple myeloma. Mil Med Res 2021, 8, 9. [Google Scholar] [CrossRef] [PubMed]
  44. Paul, B.; Rodriguez, C.; Usmani, S.Z. BCMA-targeted biologic therapies: The next standard of care in multiple myeloma therapy. Drugs 2022, 82, 613–631. [Google Scholar] [CrossRef]
  45. Pan, J.; Sun, Y.; Zhang, N.; Li, J.; Ta, F.; Wei, W.; Yu, S.; Ai, L. Characteristics of BAFF and APRIL factor expression in multiple myeloma and clinical significance. Oncol. Lett. 2017, 14, 2657–2662. [Google Scholar] [CrossRef] [PubMed]
  46. Raje, N.S.; Moreau, P.; Terpos, E.; Benboubker, L.; Grzasko, N.; Holstein, S.A.; Oriol, A.; Huang, S.Y.; Beksac, M.; Kuliczkowski, K.; et al. Phase 2 study of tabalumab, a human anti-B-cell activating factor antibody, with bortezomib and dexamethasone in patients with previously treated multiple myeloma. Br. J. Haematol. 2017, 176, 783–795. [Google Scholar] [CrossRef]
  47. Rossi, J.F.; Moreaux, J.; Hose, D.; Requirand, G.; Rose, M.; Rouille, V.; Nestorov, I.; Mordenti, G.; Goldschmidt, H.; Ythier, A.; et al. Atacicept in relapsed/refractory multiple myeloma or active Waldenstrom's macroglobulinemia: A phase I study. Br. J. Cancer 2009, 101, 1051–1058. [Google Scholar] [CrossRef]
  48. Seipel, K.; Porret, N.; Wiedemann, G.; Jeker, B.; Bacher, V.U.; Pabst, T. sBCMA plasma level dynamics and anti-BCMA CAR-T-cell treatment in relapsed multiple myeloma. Curr. Issues Mol. Biol. 2022, 44, 1463–1471. [Google Scholar] [CrossRef]
  49. Laurent, S.A.; Hoffmann, F.S.; Kuhn, P.H.; Cheng, Q.; Chu, Y.; Schmidt-Supprian, M.; Hauck, S.M.; Schuh, E.; Krumbholz, M.; Rubsamen, H.; et al. Gamma-secretase directly sheds the survival receptor BCMA from plasma cells. Nature communications 2015, 6, 7333. [Google Scholar] [CrossRef]
  50. Lonial, S.; Grosicki, S.; Hus, M.; Song, K.W.; Facon, T.; Callander, N.S.; Ribrag, V.; Uttervall, K.; Quach, H.; Vorobyev, V.I.; et al. Synergistic effects of low-dose belantamab mafodotin in combination with a gamma-secretase inhibitor (nirogacestat) in patients with relapsed/refractory multiple myeloma (RRMM): DREAMM-5 study. J. Clin. Oncol. 2022, 40, 8019. [Google Scholar] [CrossRef]
  51. Baines, A.C.; Ershler, R.; Kanapuru, B.; Xu, Q.; Shen, G.; Li, L.; Ma, L.; Okusanya, O.O.; Simpson, N.E.; Nguyen, W.; et al. FDA approval summary: Belantamab mafodotin for patients with relapsed or refractory multiple myeloma. Clin. Cancer Res. 2022, 28, 4629–4633. [Google Scholar] [CrossRef]
  52. Markham, A. Belantamab mafodotin: First approval. Drugs 2020, 80, 1607–1613. [Google Scholar] [CrossRef] [PubMed]
  53. Lonial, S.; Lee, H.C.; Badros, A.; Trudel, S.; Nooka, A.K.; Chari, A.; Abdallah, A.O.; Callander, N.; Lendvai, N.; Sborov, D.; et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): A two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2019, 21, 207–221. [Google Scholar] [CrossRef] [PubMed]
  54. GSK [press release]. London, U.K. (Nov. 22, 2022): GSK provides an update on Blenrep (belantamab mafodotin-blmf) US marketing authorization. Available online: https://www.gsk.com/en-gb/media/press-releases/gsk-provides-update-on-blenrep-us-marketing-authorisation/#:~:text=22%20November%202022-,GSK%20provides%20an%20update%20on%20Blenrep,mafodotin%2Dblmf%20US%20marketing%20authorisation&text=GSK%20plc%20(LSE%2FNYSE%3A,and%20Drug%20Administration%20(FDA) (accessed on 11 August 2023).
  55. Trudel, S.; Lendvai, N.; Popat, R.; Voorhees, P.M.; Reeves, B.; Libby, E.N.; Richardson, P.G.; Anderson, L.D., Jr.; Sutherland, H.J.; Yong, K.; et al. Targeting B-cell maturation antigen with GSK2857916 antibody-drug conjugate in relapsed or refractory multiple myeloma (BMA117159): A dose escalation and expansion phase 1 trial. Lancet Oncol. 2018, 19, 1641–1653. [Google Scholar] [CrossRef]
  56. Nooka, A.K.; Cohen, A.; Lee, H.C.; Badros, A.Z.; Suvannasankha, A.; Callander, N.; Abdallah, A.O.; Trudel, S.; Chari, A.; Libby, E.; et al. Single-agent belantamab mafodotin in patients with relapsed or refractory multiple myeloma: Final analysis of the DREAMM-2 trial. Blood 2022, 140 (Suppl. S1), 7301–7303. [Google Scholar] [CrossRef]
  57. Lonial, S.; Lee, H.C.; Badros, A.; Trudel, S.; Nooka, A.K.; Chari, A.; Abdallah, A.O.; Callander, N.; Sborov, D.; Suvannasankha, A.; et al. Longer term outcomes with single-agent belantamab mafodotin in patients with relapsed or refractory multiple myeloma: 13-month follow-up from the pivotal DREAMM-2 study. Cancer 2021, 127, 4198–4212. [Google Scholar] [CrossRef]
  58. Kortum, M.; Trudel, S.; Cohen, A.D.; Richardson, P.G.; Lonial, S.; Opalinska, J.B.; Gupta, I.; Byrne, J.; Zhi, E.; Baron, J.; et al. Safety and tolerability of single-agent belantamab mafodotin (Belamaf; GSK2857916) in heavily pre-treated patients with relapsed/refractory multiple myeloma (RRMM): Pooled data from DREAMM-1 and DREAMM-2. Oncology Research and Treatment 2020, 43, 97–98. [Google Scholar]
  59. Weisel, K.; Hopkins, T.G.; Fecteau, D.; Bao, W.; Quigley, C.; Jewell, R.C.; Nichols, M.; Opalinska, J. DREAMM-3: A phase 3, open-label, randomized study to evaluate the efficacy and safety of belantamab mafodotin (GSK2857916) monotherapy compared with pomalidomide plus low-dose dexamethasone (pom/dex) in participants with relapsed/refractory multiple myeloma (RRMM). Blood 2019, 134 (Suppl. S1), 1900. [Google Scholar] [CrossRef]
  60. Suvannasankha, A.; Bahlis, N.J.; Trudel, S.; Weisel, K.; Koenecke, C.; Rocafiguera, A.O.; Voorhees, P.M.; Alonso, A.A.; Callander, N.S.; Mateos, M.V.; et al. Safety and clinical activity of belantamab mafodotin with pembrolizumab in patients with relapsed/refractory multiple myeloma (RRMM): DREAMM-4 Study. J. Clin. Oncol. 2022, 40, 8018. [Google Scholar] [CrossRef]
  61. Weisel, K.; Richardson, P.G.; Trudel, S.; Callander, N.; Nooka, A.; Song, K.; Uttervall, K.; Minnema, M.C.; Rodriguez-Otero, P.; Struemper, H.; et al. DREAMM-5 platform trial: Belantamab Mafodotin (GSK2857916; belamaf; BLENREP) in combination with five different novel agents in patients (Pts) with relapsed/refractory multiple myeloma (RRMM). Oncology Research and Treatment 2021, 44, 204–205. [Google Scholar]
  62. Richardson, P.G.; Trudel, S.; Callander, N.S.; Nooka, A.; Song, K.; Uttervall, K.; Minnema, M.C.; Rodriguez-Otero, P.; Struemper, H.; Yeakey, A.; et al. DREAMM-5 platform trial: Belantamab mafodotin (belamaf; GSK2857916) in combination with five different novel agents in patients with relapsed/refractory multiple myeloma (RRMM). Clinical Lymphoma Myeloma & Leukemia 2021, 21, S156. [Google Scholar]
  63. Quach, H.; Gironella, M.; Lee, C.; Popat, R.; Cannell, P.; Kasinathan, R.S.; Chopra, B.; Rogers, R.; Ferron-Brady, G.; Shafi-Harji, S.; et al. Safety and clinical activity of belantamab mafodotin with lenalidomide plus dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM): DREAMM-6 Arm-A interim analysis. Clinical Lymphoma Myeloma & Leukemia 2022, 22, S423–S424. [Google Scholar]
  64. Popat, R.; Nooka, A.; Stockerl-Goldstein, K.; Abonour, R.; Ramaekers, R.; Khot, A.; Forbes, A.; Lee, C.; Augustson, B.; Spencer, A.; et al. DREAMM-6: Safety, tolerability and clinical activity of belantamab mafodotin (Belamaf) in combination with bortezomib/dexamethasone (BorDex) in relapsed/refractory multiple myeloma (RRMM). Blood 2020, 136 (Suppl. S1), 19–20. [Google Scholar] [CrossRef]
  65. Nooka, A.K.; Stockerl-Goldstein, K.; Quach, H.; Forbes, A.; Mateos, M.V.; Khot, A.; Tan, A.; Abonour, R.; Chopra, B.; Rogers, R.; et al. DREAMM-6: Safety and tolerability of belantamab mafodotin in combination with bortezomib/dexamethasone in relapsed/refractory multiple myeloma (RRMM). J. Clin. Oncol. 2020, 38 (Suppl. S15), 8502. [Google Scholar] [CrossRef]
  66. Rifkin, R.; Boyd, K.; Grosicki, S.; Kim, K.; Di Raimondo, F.; Dimopoulos, M.; Weisel, K.; Arnulf, B.; Hajek, R.; Hungria, V.; et al. DREAMM-7: A phase III study of the efficacy and safety of belantamab mafodotin with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Br. J. Haematol. 2021, 193, 172–173. [Google Scholar] [CrossRef]
  67. Rifkin, R.M.; Boyd, K.; Grosicki, S.; Kim, K.; Di Raimondo, F.; Dimopoulos, M.A.; Weisel, K.; Arnulf, B.; Hajek, R.; Hungria, V.T.M.; et al. DREAMM-7: A phase III study of the efficacy and safety of belantamab mafodotin (Belamaf) with bortezomib, and dexamethasone (B-Vd) in patients with relapsed/refractory multiple myeloma (RRMM). Blood 2020, 136 (Suppl. S1), 53–54. [Google Scholar] [CrossRef]
  68. Trudel, S.; Davis, R.; Lewis, N.M.; Bakshi, K.K.; Chopra, B.; de Oca, R.M.; Ferron-Brady, G.; Eliason, L.; Kremer, B.E.; Gupta, I.; et al. DREAMM-8: A phase III study of the efficacy and safety of belantamab mafodotin with pomalidomide and dexamethasone (B-Pd) vs pomalidomide plus bortezomib and dexamethasone (PVd) in patients with relapsed/refractory multiple myeloma (RRMM). Blood 2020, 136 (Suppl. S1), 4. [Google Scholar] [CrossRef]
  69. Trudel, S.; Davis, R.; Lewis, N.M.; Bakshi, K.K.; Chopra, B.; de Oca, R.M.; Ferron-Brady, G.; Eliason, L.; Kremer, B.E.; Stowell, D.; et al. DREAMM-8: A phase III study of the efficacy and safety of belantamab mafodotin with pomalidomide and dexamethasone vs pomalidomide plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Br. J. Haematol. 2021, 193, 177. [Google Scholar] [CrossRef]
  70. Raab, M.S.; Usmani, S.Z.; Mielnik, M.; Koh, Y.; Alonso, A.A.; Leleu, X.; Quach, H.; Min, C.K.; Janowski, W.; Abdallah, A.O.; et al. DREAMM-9: Phase I study of belantamab mafodotin with standard of care in non-transplant-eligible Patients with newly diagnosed multiple myeloma. Oncology Research and Treatment 2022, 45, 145–146. [Google Scholar]
  71. Usmani, S.Z.; Alonso, A.A.; Quach, H.; Koh, Y.; Guenther, A.; Min, C.K.; Zhou, X.O.L.; Kaisermann, M.; Mis, L.M.; Williams, D.; et al. DREAMM-9: Phase I study of belantamab mafodotin plus standard of care in patients with transplant ineligible newly diagnosed multiple myeloma. Blood 2021, 138 (Suppl. S1), 2738–2740. [Google Scholar] [CrossRef]
  72. Usmani, S.Z.; Terpos, E.; Janowski, W.; Quach, H.; West, S.; Williams, D.; Dettman, E.J.; Ferron-Brady, G.; Luptakova, K.; Gupta, I. DREAMM-9: Phase III study of belantamab mafodotin plus VRd versus VRd alone in transplant-ineligible newly diagnosed multiple myeloma (TI NDMM). J. Clin. Oncol. 2020, 38, 8556. [Google Scholar] [CrossRef]
  73. Hultcrantz, M.; Kleinman, D.; Ghataorhe, P.; McKeown, A.; He, W.; Ling, T.; Jewell, R.C.; Byrne, J.; Eliason, L.; Scott, E.C.; et al. Exploring alternative dosing regimens of single-agent belantamab mafodotin on safety and efficacy in patients with relapsed or refractory multiple myeloma: DREAMM-14. J. Clin. Oncol. 2022, 40, 8073. [Google Scholar] [CrossRef]
  74. Farooq, A.V.; Degli Esposti, S.; Popat, R.; Thulasi, P.; Lonial, S.; Nooka, A.K.; Jakubowiak, A.; Sborov, D.; Zaugg, B.E.; Badros, A.Z.; et al. Corneal epithelial findings in patients with multiple myeloma treated with antibody-drug conjugate belantamab mafodotin in the pivotal, randomized, DREAMM-2 study. Ophthalmol Ther 2020, 9, 889–911. [Google Scholar] [CrossRef]
  75. Eaton, J.S.; Miller, P.E.; Mannis, M.J.; Murphy, C.J. Ocular adverse events associated with antibody-drug conjugates in human clinical trials. J. Ocul. Pharmacol. Ther. 2015, 31, 589–604. [Google Scholar] [CrossRef] [PubMed]
  76. Fabra, Y.C.; Parot, A.A.O.; Calduch, P.; Duch-Samper, A.M. Corneal epithelial microcysts as side effect of belantamab mafodotin: Management and evolution. Acta Ophthalmol. (Copenh.) 2022, 100. [Google Scholar] [CrossRef]
  77. Mohan, M.; Rein, L.E.; Thalambedu, N.; Ogunsesan, Y.; Hussain, M.; Sethi, J.; Khan, F.; Gundarlapalli, S.; Yarlagadda, L.; Dhakal, B.; et al. Corneal toxicity with belantamab mafodotin: Multi-institutional real-life experience. Am. J. Hematol. 2022, 97, E451–E453. [Google Scholar] [CrossRef] [PubMed]
  78. Abeykoon, J.P.; Vaxman, J.; Patel, S.V.; Kumar, S.; Malave, G.C.; Young, K.S.; Ailawadhi, S.; Larsen, J.T.; Dispenzieri, A.; Muchtar, E.; et al. Impact of belantamab mafodotin-induced ocular toxicity on outcomes of patients with advanced multiple myeloma. Br. J. Haematol. 2022, 199, 95–99. [Google Scholar] [CrossRef]
  79. Mencucci, R.; Cennamo, M.; Alonzo, L.; Senni, C.; Vagge, A.; Ferro Desideri, L.; Scorcia, V.; Giannaccare, G. Corneal findings associated to belantamab-mafodotin (Belamaf) use in a series of patients examined longitudinally by means of advanced corneal imaging. Journal of clinical medicine 2022, 11, 2884. [Google Scholar] [CrossRef]
  80. Pahl, A.; Lutz, C.; Hechler, T. Amanitins and their development as a payload for antibody-drug conjugates. Drug Discov Today Technol 2018, 30, 85–89. [Google Scholar] [CrossRef]
  81. Kaufman, J.L.; Orlowski, R.Z.; Strassz, A.; Pahl, A.; Michaels, T.; Last, A.; Szaboki, H.; Jentsch, G.; Schoenborn-Kellenberger, O.; Raab, M.S. HDP-101, an anti-BCMA antibody-drug conjugate with a novel payload amanitin in patients with relapsed multiple myeloma, initial findings of the first in human study. Blood 2022, 140 (Suppl. S1), 7235–7236. [Google Scholar] [CrossRef]
  82. Lee, H.C.; Raje, N.S.; Landgren, O.; Upreti, V.V.; Wang, J.; Avilion, A.A.; Hu, X.G.; Rasmussen, E.; Ngarmchamnanrith, G.; Fujii, H.; et al. Phase 1 study of the anti-BCMA antibody-drug conjugate AMG 224 in patients with relapsed/refractory multiple myeloma. Leukemia 2021, 35, 255–258. [Google Scholar] [CrossRef] [PubMed]
  83. Chakraborty, R.; Yan, Y.; Royal, M. A phase 1, open-label, dose-escalation study of the safety and efficacy of anti-CD38 antibody drug conjugate (STI-6129) in patients with relapsed or refractory multiple myeloma. Blood 2021, 138 (Suppl. S1), 4763. [Google Scholar] [CrossRef]
  84. Kaufman, J.; Atrash, S.; Benson, D.; Holstein, S.; Nadeem, O.; Biran, N.; Suryanarayan, K.; Liu, Y.Y.; Robinson, L.; Correa, K.; et al. A randomized phase 2 study of modakafusp alfa (TAK-573) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) with a pilot diversity, equity, and inclusion (DEI) strategy. Clinical Lymphoma Myeloma & Leukemia 2022, 22, S42. [Google Scholar]
  85. Dholaria, B.; Mamuye, A.; Yurewicz, D.; Dabovic, K.; Yuet, A.; Abonour, R.; Kelly, K.R.; Voorhees, T.J.; Kazandjian, D. A phase 1, open-label, dose-escalation and expansion, multicenter study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of MT-0169 in patients with relapsed or refractory multiple myeloma or non-Hodgkin lymphoma. Blood 2022, 140 (Suppl. S1), 12621–12622. [Google Scholar] [CrossRef]
  86. Wong, S.; Imus, P.; Mark, T.; Kaufman, J.; Imus, A.; Zonder, J.A.; Walker, Z.; Sherbenou, D.; Schroeder, M.; Abbey, J.; et al. A first-in-human study of FOR46 in patients with triple refractory multiple myeloma. Clinical Lymphoma Myeloma & Leukemia 2021, 21, S164. [Google Scholar]
  87. Kelly, K.R.; Ailawadhi, S.; Siegel, D.S.; Heffner, L.T.; Somlo, G.; Jagannath, S.; Zimmerman, T.M.; Munshi, N.C.; Madan, S.; Chanan-Khan, A.; et al. Indatuximab ravtansine plus dexamethasone with lenalidomide or pomalidomide in relapsed or refractory multiple myeloma: A multicentre, phase 1/2a study. The Lancet. Haematology 2021, 8, e794–e807. [Google Scholar] [CrossRef]
  88. Huang, W.; Luo, J.; Li, Y.; Fei, D.; Qin, X.; Li, R. Preclinical activity of LM-305 targeting G-protein-coupled receptor class 5 member D (GPRC5D) antibody drug conjugate for the treatment of multiple myeloma. Cancer Res. 2022, 82 (12 Supplement), 6020. [Google Scholar] [CrossRef]
  89. Shah, N.N.; Krishnan, A.Y.; Shah, N.D.; Burke, J.M.; Melear, J.M.; Spira, A.I.; Kaufman, J.L.; Cohen, J.B.; Niesvizky, R.; Popplewell, L.L.; et al. A phase I open-label, safety, pharmacokinetic, and preliminary efficacy study of STRO-001, an anti-CD74 antibody drug conjugate, in patients with advanced B-cell malignancies. Cancer Res. 2019, 79, CT104. [Google Scholar] [CrossRef]
  90. Krishnan, A.Y.; Shah, N.; Spira, A.I.; Kaufman, J.L.; Niesvizky, R.; Shah, N.N.; Burke, J.M.; Popplewell, L.; Martin, T.G.; Cheung, J.; et al. A phase 1 open-label, safety, pharmacokinetic, and preliminary efficacy study of STRO-001, an anti-CD74 antibody drug conjugate, in patients with advanced B-cell malignancies. J. Clin. Oncol. 2018, 36, TPS7586. [Google Scholar] [CrossRef]
  91. Nisonoff, A.; Rivers, M.M. Recombination of a mixture of univalent antibody fragments of different specificity. Arch. Biochem. Biophys. 1961, 93, 460–462. [Google Scholar] [CrossRef]
  92. Voskoboinik, I.; Whisstock, J.C.; Trapani, J.A. Perforin and granzymes: Function, dysfunction and human pathology. Nat. Rev. Immunol. 2015, 15, 388–400. [Google Scholar] [CrossRef]
  93. Mandikian, D.; Takahashi, N.; Lo, A.A.; Li, J.; Eastham-Anderson, J.; Slaga, D.; Ho, J.; Hristopoulos, M.; Clark, R.; Totpal, K.; et al. Relative target affinities of T-cell-dependent bispecific antibodies determine biodistribution in a solid tumor mouse model. Mol. Cancer Ther. 2018, 17, 776–785. [Google Scholar] [CrossRef] [PubMed]
  94. Mazor, Y.; Sachsenmeier, K.F.; Yang, C.; Hansen, A.; Filderman, J.; Mulgrew, K.; Wu, H.; Dall'Acqua, W.F. Enhanced tumor-targeting selectivity by modulating bispecific antibody binding affinity and format valence. Sci. Rep. 2017, 7, 40098. [Google Scholar] [CrossRef] [PubMed]
  95. Baeuerle, P.A.; Reinhardt, C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. 2009, 69, 4941–4944. [Google Scholar] [CrossRef]
  96. Velders, M.P.; van Rhijn, C.M.; Oskam, E.; Fleuren, G.J.; Warnaar, S.O.; Litvinov, S.V. The impact of antigen density and antibody affinity on antibody-dependent cellular cytotoxicity: Relevance for immunotherapy of carcinomas. Br. J. Cancer 1998, 78, 478–483. [Google Scholar] [CrossRef] [PubMed]
  97. Moreau, P.; Garfall, A.L.; van de Donk, N.; Nahi, H.; San-Miguel, J.F.; Oriol, A.; Nooka, A.K.; Martin, T.; Rosinol, L.; Chari, A.; et al. Teclistamab in relapsed or refractory multiple myeloma. N. Engl. J. Med. 2022, 387, 495–505. [Google Scholar] [CrossRef]
  98. Touzeau, C.; Krishnan, A.Y.; Moreau, P.; Perrot, A.; Usmani, S.Z.; Manier, S.; Cavo, M.; Martinez-Chamorro, C.; Nooka, A.K.; Martin, T.G.; et al. Efficacy and safety of teclistamab (tec), a B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in patients (pts) with relapsed/refractory multiple myeloma (RRMM) after exposure to other BCMA-targeted agents. J. Clin. Oncol. 2022, 40 (16 suppl), 8013. [Google Scholar] [CrossRef]
  99. Popat, R.; Usmani, S.Z.; Garfall, A.; van de Donk, N.; Nahi, H.; San-Miguel, J.F.; Oriol, A.; Nooka, A.; Martin, T.; Rosinol, L.; et al. Updated results from the phase 1/2 MajesTEC-1 study of teclistamab, a B-cell maturation antigen x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma. Br. J. Haematol. 2022, 197, 35–36. [Google Scholar] [CrossRef]
  100. Moreau, P.; Usmani, S.Z.; Garfall, A.L.; de Donk, N.W.V.; Nahi, H.; San-Miguel, J.; Oriol, A.; Nooka, A.K.; Martin, T.; Rosino, L.; et al. Updated results from MajesTEC-1: Phase 1/2 study of teclistamab, a B-cell maturation antigen x CD3 bispecific antibody, in relapsed/refractory multiple myeloma. Blood 2021, 138 (Suppl. S1), 896. [Google Scholar] [CrossRef]
  101. Miao, X.; Wu, L.S.; Lin, S.X.W.; Xu, Y.; Chen, Y.; Iwaki, Y.; Kobos, R.; Stephenson, T.; Kemmerer, K.; Uhlar, C.M.; et al. Teclistamab population pharmacokinetics and exposure-response relationship support 1.5 mg/kg dose regimen in relapsed/refractory multiple myeloma. Blood 2022, 140 (Suppl. S1)）, 4382–4383. [Google Scholar] [CrossRef]
  102. Searle, E.; Quach, H.; Wong, S.W.; Costa, L.J.; Hulin, C.; Janowski, W.; Berdeja, J.; Anguille, S.; Matous, J.V.; Touzeau, C.; et al. Teclistamab in combination with subcutaneous daratumumab and lenalidomide in patients with multiple myeloma: Results from one cohort of MajesTEC-2, a phase1b, multicohort study. Blood 2022, 140 (Suppl. S1), 394–396. [Google Scholar] [CrossRef]
  103. Searle, E.; Quach, H.; Wong, S.; Costa, L.; Hulin, C.; Janowski, W.; Berdeja, J.; Anguille, S.; Matous, J.; Touzeau, C.; et al. Single cohort results from MajesTEC-2: Teclistamab (tec) in combination with subcutaneous daratumumab (dara) and lenalidomide. HemeSphere 2023, 7, 27. [Google Scholar] [CrossRef]
  104. Mateos, M.V.; Bahlis, N.J.; Costa, L.J.; Perrot, A.; Pei, L.; Rubin, M.L.; Lantz, K.; Sun, W.; Jaffe, M.; Kobos, R.; et al. MajesTEC-3: Randomized, phase 3 study of teclistamab plus daratumumab versus investigator's choice of daratumumab, pomalidomide, and dexamethasone or daratumumab, bortezomib, and dexamethasone in patients with relapsed/refractory multiple myeloma. J. Clin. Oncol. 2022, 40, TPS8072. [Google Scholar] [CrossRef]
  105. Zamagni, E.; Boccadoro, M.; Spencer, A.; Delforge, M.; Reece, D.E.; Szabo, A.G.; Einsele, H.; Terpos, E.; Schjesvold, F.; Bila, J.; et al. MajesTEC-4 (EMN30): A phase 3 trial of teclistamab plus lenalidomide versus lenalidomide alone as maintenance therapy following autologous stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood 2022, 140 (Suppl. S1), 7289–7291. [Google Scholar] [CrossRef]
  106. Krishnan, A.Y.; Manier, S.; Terpos, E.; Usmani, S.; Khan, J.; Pearson, R.; Girgis, S.; Guo, Y.; McAleer, D.; Olyslager, Y.; et al. MajesTEC-7: A phase 3, randomized study of teclistamab plus daratumumab plus lenalidomide (Tec-DR) versus daratumumab plus lenalidomide plus dexamethasone (DRd) in patients with newly diagnosed multiple myeloma who are either ineligible or not intended for autologous stem cell transplant. Blood 2022, 140 (Suppl. S1), 10148–10149. [Google Scholar] [CrossRef]
  107. Rodriguez-Otero, P.; D'Souza, A.; Reece, D.E.; van de Donk, N.; Chari, A.; Krishnan, A.Y.; Martin, T.G.; Mateos, M.V.; Morillo, D.; Hurd, D.D.; et al. A novel, immunotherapy-based approach for the treatment of relapsed/refractory multiple myeloma (RRMM): Updated phase 1b results for daratumumab in combination with teclistamab (a BCMA x CD3 bispecific antibody). J. Clin. Oncol. 2022, 40, 8032. [Google Scholar] [CrossRef]
  108. Rodriguez-Otero, P.; Dholaria, B.; Askari, E.; Reece, D.E.; de Donk, N.; Chari, A.; Goldschmidt, H.; Krishnan, A.Y.; Martin, T.; Mateos, M.V.; et al. Subcutaneous teclistamab in combination with daratumumab for the treatment of patients with relapsed/refractory multiple myeloma: Results from a phase 1b multicohort study. Blood 2021, 138 (Suppl. S1), 1647. [Google Scholar] [CrossRef]
  109. U.S. Food and Drug Administration [press release]. Washington, D.C. (Aug. 14, 2023): FDA grants accelerated approval to elranatamab-bcmm for multiple myeloma. Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-elranatamab-bcmm-multiple-myeloma (accessed on 19 August 2023).
  110. Lesokhin, A.M.; Tomasson, M.H.; Arnulf, B.; Bahlis, N.J.; Miles Prince, H.; Niesvizky, R.; Rodrίguez-Otero, P.; Martinez-Lopez, J.; Koehne, G.; Touzeau, C.; et al. Elranatamab in relapsed or refractory multiple myeloma: Phase 2 MagnetisMM-3 trial results. Nat. Med. Published online ahead of print. 2023. [Google Scholar] [CrossRef]
  111. Raje, N.; Bahlis, N.J.; Costello, C.; Dholaria, B.; Solh, M.; Levy, M.Y.; Tomasson, M.H.; Damore, M.A.; Jiang, S.B.; Basu, C.; et al. Elranatamab, a BCMA targeted T-cell engaging bispecific antibody, induces durable clinical and molecular responses for patients with relapsed or refractory multiple myeloma. Blood 2022, 140 (Suppl. S1), 388–390. [Google Scholar] [CrossRef]
  112. Jakubowiak, A.J.; Bahlis, N.J.; Raje, N.S.; Costello, C.; Dholaria, B.R.; Solh, M.M.; Levy, M.Y.; Tomasson, M.H.; Dube, H.; Damore, M.A.; et al. Elranatamab, a BCMA-targeted T-cell redirecting immunotherapy, for patients with relapsed or refractory multiple myeloma: Updated results from MagnetisMM-1. J. Clin. Oncol. 2022, 40, 8014. [Google Scholar] [CrossRef]
  113. Landgren, O.; Kazandjian, D.; O'Connell, A.; Finn, G.; Raje, N. Magnetismm-4: An open label, phase 1b/2 umbrella study of elranatamab in combination with other anti-cancer treatments for patients with multiple myeloma. Blood 2022, 140 (Suppl. S1), 10172–10173. [Google Scholar] [CrossRef]
  114. Grosicki, S.; Mellqvist, U.H.; Pruchniewski, L.; Crafoord, J.; Trudel, S.; Min, C.K.; White, D.; Alegre, A.; Hansson, M.; Ikeda, T.; et al. Elranatamab in combination with daratumumab for patients (pts) with relapsed/refractory multiple myeloma (RRMM): Results from the phase 3 Magnetismm-5 study safety lead-in cohort. Blood 2022, 140 (Suppl. S1), 4407–4408. [Google Scholar] [CrossRef]
  115. Grosicki, S.; Crafoord, J.; Koh, Y.; White, D.; Mellqvist, U.H.; Leip, E.; Kudla, A.; Finn, G.; Pruchniewski, L. MagnetisMM-5: An open-label, multicenter, randomized phase 3 study of elranatamab as monotherapy and in combination with daratumumab in patients with relapsed/refractory multiple myeloma. J. Clin. Oncol. 2022, 40, TPS8074. [Google Scholar] [CrossRef]
  116. Mateos, M.V.; Lee, J.H.; Manier, S.; Vandendries, E.; Benner, R.; Yver, A. MagnetisMM-7: An open label, randomized, phase 3 study of elranatamab versus lenalidomide in patients with newly diagnosed multiple myeloma who are minimal residual disease-positive after transplant. Clinical Lymphoma Myeloma & Leukemia 2022, 22, S45. [Google Scholar]
  117. Prager, I.; Watzl, C. Mechanisms of natural killer cell-mediated cellular cytotoxicity. J. Leukoc. Biol. 2019, 105, 1319–1329. [Google Scholar] [CrossRef] [PubMed]
  118. Plesner, T.; Harrison, S.J.; Quach, H.; Lee, C.; Bryant, A.; Vangsted, A.; Estell, J.; Delforge, M.; Offner, F.; Twomey, P.; et al. Phase I study of safety and pharmacokinetics of RO7297089, an anti-BCMA/CD16a bispecific antibody, in patients with relapsed, refractory multiple myeloma. Clin Hematol Int 2023, 5, 43–51. [Google Scholar] [CrossRef]
  119. Cooper, D.; Madduri, D.; Lentzsch, S.; Jagannath, S.; Li, J.; Boyapati, A.; Adriaens, L.; Chokshi, D.; Zhu, M.; Lowy, I.; et al. Safety and preliminary clinical activity of REGN5458, an anti-BCMA x anti-CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma. Blood 2019, 134 (Suppl. S1), 3176. [Google Scholar] [CrossRef]
  120. Surowka, M.; Schaefer, W.; Klein, C. Ten years in the making: Application of CrossMab technology for the development of therapeutic bispecific antibodies and antibody fusion proteins. mAbs 2021, 13, 1967714. [Google Scholar] [CrossRef]
  121. Paiva, B.; Gaffney, B.; Burnett, K.; Castiglioni, P.; Angelo, M.; Pierce, D.W.; Boss, I.W. Synergistic antitumor activity of alnuctamab (Alnuc; BMS-986349; CC-93269), a BCMA 2+1 T cell engager (TCE), and celmod agents in multiple myeloma (MM) preclinical models. Blood 2022, 140 (Suppl. S1), 7054–7055. [Google Scholar] [CrossRef]
  122. Law, C.L.; Aaron, W.; Austin, R.; Barath, M.; Callihan, E.; Evans, T.; Gamez Guerrero, M.; Hemmati, G.; Jones, A.; Kwant, K.; et al. Preclinical and nonclinical characterization of HPN217: A tri-specific T cell activating construct (TriTAC) targeting B cell maturation antigen (BCMA) for the treatment of multiple myeloma. Blood 2018, 132 (Suppl. S1), 3225. [Google Scholar] [CrossRef]
  123. Voorhees, P.M.; D'Souza, A.; Weisel, K.; Hurd, D.D.; Teipel, R.; Chung, A.; Rodriguez, C.; Tuchman, S.A.; Korde, N.; Safah, H.; et al. A phase 1 first-in-human study of ABBV-383, a BCMA x CD3 bispecific T-cell-redirecting antibody, as monotherapy in patients with relapsed/refractory multiple myeloma. Blood 2022, 140 (Suppl. S1), 4401–4404. [Google Scholar] [CrossRef]
  124. Raab, M.S.; Cohen, Y.C.; Schjesvold, F.; Aardalen, K.; Oka, A.; Spencer, A.; Wermke, M.; Souza, A.D.; Kaufman, J.L.; Cafro, A.M.; et al. Preclinical discovery and initial clinical data of WVT078, a BCMA × CD3 bispecific antibody. Leukemia 2023, 37, 1349–1360. [Google Scholar] [CrossRef] [PubMed]
  125. Rodriguez, C.; Weisel, K.; Baz, R.C.; Polepally, A.R.; Ross, J.A.; Jin, Z.Y.; D'Amico, K.; Bueno, O.F.; Fleming, L.L.; Voorhees, P.M. Dose escalation and expansion of ABBV-383 in combination with anti-cancer regimens in relapsed or refractory multiple myeloma. Blood 2022, 140 (Suppl. S1), 7326–7327. [Google Scholar] [CrossRef]
  126. Wong, S.W.; Bar, N.; Paris, L.; Hofmeister, C.C.; Hansson, M.; Santoro, A.; Mateos, M.V.; Rodriguez-Otero, P.; Lund, J.; Encinas, C.; et al. Alnuctamab (ALNUC.; BMS-986349; CC-93269), a B-Cell Maturation Antigen (BCMA) x CD3 T-Cell Engager (TCE), in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Results from a phase 1 first-in-human clinical study. Blood 2022, 140 (Suppl. S1), 400–402. [Google Scholar] [CrossRef]
  127. Zonder, J.A.; Richter, J.; Bumma, N.; Brayer, J.; Hoffman, J.E.; Bensinger, W.I.; Wu, K.L.; Xu, L.; Chokshi, D.; Boyapati, A.; et al. Early, deep, and durable responses, and low rates of cytokine release syndrome with REGN5458, a BCMAxCD3 bispecific antibody, in a phase 1/2 first-in-human study in patients with relapsed/refractory multiple myeloma. Clin. Lymphoma Myeloma Leuk. 2022, 22 (Suppl. S2), S406–s407. [Google Scholar] [CrossRef]
  128. Bumma, N.; Richter, J.; Brayer, J.; Zonder, J.A.; Dhodapkar, M.; Shah, M.R.; Hoffman, J.E.; Mawad, R.; Maly, J.J.; Lentzsch, S.; et al. Updated safety and efficacy of REGN5458, a BCMAxCD3 bispecific antibody, treatment for relapsed/refractory multiple myeloma: A phase 1/2 first-in-human study. Blood 2022, 140 (Suppl. S1), 10140–10141. [Google Scholar] [CrossRef]
  129. Zonder, J.A.; Richter, J.; Bumma, N.; Brayer, J.; Hoffman, J.E.; Bensinger, W.I.; Wu, K.L.; Xu, L.Z.; Chokshi, D.; Boyapati, A.; et al. Early, deep, and durable responses, and low rates of cytokine release syndrome with REGN5458, a BCMAxCD3 bispecific monoclonal antibody, in a phase 1/2 first-in-human study in patients with relapsed/refractory multiple myeloma (RRMM). Blood 2021, 138 (Suppl. S1), 160. [Google Scholar] [CrossRef]
  130. Suvannasankha, A.; Kapoor, P.; Pianko, M.J.; Richter, J.; D'Souza, A.; Anderson Jr., L. D.; Magyar, A.; Aina, O.; Boyapati, A.; Cronier, D.; et al. Safety and efficacy from the phase 1/2 first-in-human study of REGN5459, a BCMA×CD3 bispecific antibody with low CD3 affinity, in patients with relapsed/refractory multiple myeloma. Cancer Res. 2023, 83, CT013. [Google Scholar] [CrossRef]
  131. Kumar, S.; D'Souza, A.; Shah, N.; Rodriguez, C.; Voorhees, P.M.; Bueno, O.F.; Ben, B.; Freise, K.J.; Yue, S.; Pothacamury, R.K.; et al. A phase 1 first-in-human study of TNB-383B, a BCMA x CD3 bispecific T-cell redirecting antibody, in patients with relapsed/refractory multiple myeloma. Blood 2021, 138 (Suppl. S1), 900. [Google Scholar] [CrossRef]
  132. Abdallah, A.O.; Cowan, A.J.; Leleu, X.; Touzeau, C.; Lipe, B.; Medvedova, E.; Costello, C.; Hillengass, J.; Bergsagel, P.L.; Mawad, R.; et al. Updated interim results from a phase 1 study of HPN217, a half-life extended tri-specific T cell activating construct (TriTAC (R)) targeting B cell maturation antigen (BCMA) for relapsed/refractory multiple myeloma (RRMM). Blood 2022, 140 (Suppl. S1), 7284–7285. [Google Scholar] [CrossRef]
  133. Nath, K.; Costa, B.A.; Mailankody, S. GPRC5D as a novel immunotherapeutic target in multiple myeloma. Nat. Rev. Clin. Oncol. 2023, 20, 281–282. [Google Scholar] [CrossRef] [PubMed]
  134. Atamaniuk, J.; Gleiss, A.; Porpaczy, E.; Kainz, B.; Grunt, T.W.; Raderer, M.; Hilgarth, B.; Drach, J.; Ludwig, H.; Gisslinger, H.; et al. Overexpression of G protein-coupled receptor 5D in the bone marrow is associated with poor prognosis in patients with multiple myeloma. Eur. J. Clin. Invest. 2012, 42, 953–960. [Google Scholar] [CrossRef] [PubMed]
  135. U.S. Food and Drug Administration [press release]. Washington, D.C. (Aug. 9, 2023): FDA grants accelerated approval to talquetamab-tgvs for relapsed or refractory multiple myeloma. Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-talquetamab-tgvs-relapsed-or-refractory-multiple-myeloma (accessed on 11 August 2023).
  136. Cohen, Y.C.; Moreau, P.; Tolbert, J.; Qin, X.; Ma, X.W.; Vieyra, D.; Langlois, A.; Courtoux, C.; Terry, W.; Pei, L.X.; et al. MonumenTAL-3: Phase 3 trial of talquetamab plus daratumumab +/- pomalidomide versus daratumumab plus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma following > 1 prior line of therapy. Blood 2022, 140 (Suppl. S1), 4418–4419. [Google Scholar] [CrossRef]
  137. Chari, A.; Minnema, M.C.; Berdeja, J.G.; Oriol, A.; van de Donk, N.; Rodríguez-Otero, P.; Askari, E.; Mateos, M.V.; Costa, L.J.; Caers, J.; et al. Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. N. Engl. J. Med. 2022, 387, 2232–2244. [Google Scholar] [CrossRef] [PubMed]
  138. Minnema, M.C.; Krishnan, A.Y.; Berdeja, J.G.; Rocafiguera, A.O.; van de Donk, N.; Rodriguez-Otero, P.; Morillo, D.; Mateos, M.V.; Costa, L.J.; Caers, J.; et al. Efficacy and safety of talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): Updated results from MonumenTAL-1. J. Clin. Oncol. 2022, 40, 8015. [Google Scholar] [CrossRef]
  139. Krishnan, A.Y.; Minnema, M.C.; Berdeja, J.G.; Oriol, A.; van de Donk, N.; Rodriguez-Otero, P.; Askari, E.; Mateos, M.V.; Costa, L.J.; Verona, R.I.; et al. Updated phase 1 results from MonumenTAL-1: First-in-human study of talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma. Blood 2021, 138 (Suppl. S1), 158. [Google Scholar] [CrossRef]
  140. Berdeja, J.G.; Krishnan, A.Y.; Oriol, A.; van de Donk, N.; Rodriguez-Otero, P.; Askari, E.; Mateos, M.V.; Minnema, M.C.; Costa, L.J.; Verona, R.; et al. Updated results of a phase 1, first-in-human study of talquetamab, a G protein-coupled receptor family C group 5 member D (GPRC5D) x CD3 bispecific antibody, in relapsed/refractory multiple myeloma (MM). J. Clin. Oncol. 2021, 39, 8008. [Google Scholar] [CrossRef]
  141. van de Donk, N.W.C.; Minnema, M.; Berdeja, J.; Oriol, A.; Krishnan, A.; Rodríguez-Otero, P.; Askari, E.; Mateos, M.; Costa, L.; Verona, R.; et al. Talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): Updated phase 1 results from MONUMENTAL-1. HemaSphere 2022, 6, 16–17. [Google Scholar] [CrossRef]
  142. van de Donk, N.W.; Bahlis, N.; Mateos, M.-V.; Weisel, K.; Dholaria, B.; Garfall, A.L.; Goldschmidt, H.; Martin, T.G.; Morillo, D.; Reece, D.E.; et al. Novel combination immunotherapy for the treatment of relapsed/refractory multiple myeloma: Updated phase 1b results for talquetamab (a GPRC5D x CD3 bispecific antibody) in combination with daratumumab. HemaSphere 2022, 6, 84–85. [Google Scholar] [CrossRef]
  143. Mateos, M.; Hari, P.; Bahlis, N.; Chari, A.; van de Donk, N.; Dholaria, B.; Garfall, A.L.; Goldschmidt, H.; Kortüm, K.M.; Krishnan, A.; et al. Subcutaneous talquetamab in combination with daratumumab in patients with relapsed/refractory multiple myeloma (RRMM): Phase 1b results. HemaSphere 2022, 6, 9. [Google Scholar] [CrossRef]
  144. Eckmann, J.; Fauti, T.; Zabaleta, A.; Blanco, L.; Kassem, S.; Carrie, N.; Lorenz, S.; Carpy, A.; Christopeit, T.; Fertig, G.; et al. RG6234: A novel 2:1 GPRC5D T cell bispecific antibody exhibits best in class potential for the treatment of multiple myeloma as a monotherapy and in combination. Blood 2022, 140 (Suppl. S1), 2091–2092. [Google Scholar] [CrossRef]
  145. Carlo-Stella, C.; Mazza, R.; Manier, S.; Facon, T.; Yoon, S.S.; Koh, Y.; Harrison, S.J.; Er, J.; Pinto, A.; Volzone, F.; et al. RG6234, a GPRC5DxCD3 T-cell engaging bispecific antibody, is highly active in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Updated intravenous (IV) and first subcutaneous (SC) results from a phase I dose-escalation study. Blood 2022, 140 (Suppl. S1), 397–399. [Google Scholar] [CrossRef]
  146. Li, J.; Stagg, N.J.; Johnston, J.; Harris, M.J.; Menzies, S.A.; DiCara, D.; Clark, V.; Hristopoulos, M.; Cook, R.; Slaga, D.; et al. Membrane-proximal epitope facilitates efficient T cell synapse formation by anti-FcRH5/CD3 and is a requirement for myeloma cell killing. Cancer Cell 2017, 31, 383–395. [Google Scholar] [CrossRef]
  147. Trudel, S.; Bahlis, N.J.; Spencer, A.; Kaedbey, R.; Otero, P.R.; Harrison, S.J.; Wong, C.; Goodman, G.R.; Nakamura, R.; Choeurng, V.; et al. Pretreatment with tocilizumab prior to the CD3 bispecific cevostamab in patients with relapsed/refractory multiple myeloma (RRMM) showed a marked reduction in cytokine release syndrome incidence and severity. Blood 2022, 140 (Suppl. S1), 1363–1365. [Google Scholar] [CrossRef]
  148. Delimpasi, S.; Quach, H.; Cavo, M.; Ho, P.J.; Lee, C.; Santoro, A.; Schots, R.; Vlummens, P.; Yoon, D.H.; Yoon, S.S.; et al. CAMMA 3: A multicenter phase Ib trial evaluating the safety, pharmacokinetics, and activity of subcutaneous cevostamab monotherapy in patients with relapsed or refractory multiple myeloma. J. Clin. Oncol. 2022, 40, TPS8070. [Google Scholar] [CrossRef]
  149. Trudel, S.; Cohen, A.D.; Krishnan, A.Y.; Fonseca, R.; Spencer, A.; Berdeja, J.G.; Lesokhin, A.; Forsberg, P.A.; Laubach, J.P.; Costa, L.J.; et al. Cevostamab monotherapy continues to show clinically meaningful activity and manageable safety in patients with heavily pre-treated relapsed/refractory multiple myeloma (RRMM): Updated results from an ongoing phase 1 study. Blood 2021, 138 (Suppl. S1), 157. [Google Scholar] [CrossRef]
  150. Vij, R.; Schade, H.; Trudel, S.; Chang, A.C.; Huang, J.; Samineni, D.; Sumiyoshi, T.; Tsai, J.; Wong, T.; Harrison, S.J. CAMMA 1: A multicenter phase Ib trial evaluating the safety, pharmacokinetics, and activity of cevostamab-containing regimens in patients with relapsed or refractory multiple myeloma. J. Clin. Oncol. 2022, 40, TPS8069. [Google Scholar] [CrossRef]
  151. Pouleau, B.; Estoppey, C.; Suere, P.; Nallet, E.; Laurendon, A.; Monney, T.; Pais Ferreira, D.; Drake, A.; Carretero-Iglesia, L.; Macoin, J.; et al. Pre-clinical characterization of ISB 1342, a CD38xCD3 T-cell engager for relapsed/refractory multiple myeloma. Blood 2023, 142, 260–273. [Google Scholar] [CrossRef]
  152. Mohan, S.R.; Chase, C.C.; Berdeja, J.G.; Karlin, L.; Belhadj, K.; Perrot, A.; Moreau, P.; Touzeau, C.; Chalopin, T.; Lesokhin, A.M.; et al. Initial results of dose escalation of ISB 1342, a novel CD3xCD38 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM). Blood 2022, 140 (Suppl. S1), 7264–7266. [Google Scholar] [CrossRef]
  153. Zheng, Y.; Yang, J.; Qian, J.; Qiu, P.; Hanabuchi, S.; Lu, Y.; Wang, Z.; Liu, Z.; Li, H.; He, J.; et al. PSGL-1/selectin and ICAM-1/CD18 interactions are involved in macrophage-induced drug resistance in myeloma. Leukemia 2013, 27, 702–710. [Google Scholar] [CrossRef] [PubMed]
  154. Chen, X.C.; Wong, O.K.; Post, L. Multiple modes of action of the CD38 x ICAM-1 bispecific antibody. Cancer Res. 2022, 82, 5385. [Google Scholar] [CrossRef]
  155. Stefano, S.; Grandclement, C.; Dehilly, E.; Panagopoulou, M.; Martini, E.; Castillo, R.; Suere, P.; Pouleau, B.; Estoppey, C.; Frei, J.; et al. ISB 1442, a first-in-class CD38 and CD47 bispecific antibody innate cell modulator for the treatment of relapsed refractory multiple myeloma. Blood 2021, 138 (Suppl. S1), 73. [Google Scholar] [CrossRef]
  156. Sia, H.; Tan, P.T.; Richter, J.; Ho, P.J.; Cochrane, T.; Quach, H.; Dhakal, B.; Proscurshim, I.; Jiang, T.; Mancino, E.; et al. A phase 1/2, first-in-human, multicenter, open-label, dose escalation and dose-expansion study of single-agent ISB 1442 in patients with relapsed/refractory multiple myeloma. Blood 2022, 140 (Suppl. S1), 10182–10184. [Google Scholar] [CrossRef]
  157. El-Murr, N.; Henry, C.; Francesconi, E.; Attenot, F.; Virone-Oddos, A.; Vidard, L.; Wu, L.; Yang, Z.-Y.; Chiron, M. CD28 expression on multiple myeloma cells enhances the cytotoxic activity of CD38/CD28xCD3 trispecific T cell engager. Cancer Res. 2020, 80, 5641. [Google Scholar] [CrossRef]
  158. Khanam, R.; Ashruf, O.S.; Waqar, S.H.B.; Shah, Z.; Batool, S.; Mehreen, R.; Pachika, P.; Roksana, Z.; Rehman, M.E.U.; Anwer, F. The role of bispecific antibodies in relapsed refractory multiple myeloma: A systematic review. Antibodies (Basel, Switzerland) 2023, 12, 38. [Google Scholar] [CrossRef]
  159. Tang, H.K.C.; Wang, B.; Tan, H.X.; Sarwar, M.A.; Baraka, B.; Shafiq, T.; Rao, A.R. CAR T-cell therapy for cancer: Latest updates and challenges, with a focus on B-lymphoid malignancies and selected solid tumours. Cells 2023, 12, 1586. [Google Scholar] [CrossRef] [PubMed]
  160. Chen, C.; Liu, X.; Chang, C.Y.; Wang, H.Y.; Wang, R.F. The interplay between T cells and cancer: The basis of immunotherapy. Genes (Basel) 2023, 14, 1008. [Google Scholar] [CrossRef]
  161. Huang, R.; Li, X.; He, Y.; Zhu, W.; Gao, L.; Liu, Y.; Gao, L.; Wen, Q.; Zhong, J.F.; Zhang, C.; et al. Recent advances in CAR-T cell engineering. J. Hematol. Oncol. 2020, 13, 86. [Google Scholar] [CrossRef]
  162. Garfall, A.L.; Stadtmauer, E.A.; Hwang, W.T.; Lacey, S.F.; Melenhorst, J.J.; Krevvata, M.; Carroll, M.P.; Matsui, W.H.; Wang, Q.; Dhodapkar, M.V.; et al. Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma. JCI insight 2018, 3, e120505. [Google Scholar] [CrossRef]
  163. Schuster, S.J.; Bishop, M.R.; Tam, C.S.; Waller, E.K.; Borchmann, P.; McGuirk, J.P.; Jäger, U.; Jaglowski, S.; Andreadis, C.; Westin, J.R.; et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 2019, 380, 45–56. [Google Scholar] [CrossRef]
  164. Locke, F.L.; Ghobadi, A.; Jacobson, C.A.; Miklos, D.B.; Lekakis, L.J.; Oluwole, O.O.; Lin, Y.; Braunschweig, I.; Hill, B.T.; Timmerman, J.M.; et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): A single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019, 20, 31–42. [Google Scholar] [CrossRef] [PubMed]
  165. Abramson, J.S.; Gordon, L.I.; Palomba, M.L.; Lunning, M.A.; Arnason, J.E.; Forero-Torres, A.; Wang, M.; Maloney, D.G.; Sehgal, A.; Andreadis, C.; et al. Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL. J. Clin. Oncol. 2018, 36, 7505. [Google Scholar] [CrossRef]
  166. Neelapu, S.S.; Locke, F.L.; Bartlett, N.L.; Lekakis, L.J.; Miklos, D.B.; Jacobson, C.A.; Braunschweig, I.; Oluwole, O.O.; Siddiqi, T.; Lin, Y.; et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 2017, 377, 2531–2544. [Google Scholar] [CrossRef] [PubMed]
  167. Amini, L.; Silbert, S.K.; Maude, S.L.; Nastoupil, L.J.; Ramos, C.A.; Brentjens, R.J.; Sauter, C.S.; Shah, N.N.; Abou-El-Enein, M. Preparing for CAR T cell therapy: Patient selection, bridging therapies and lymphodepletion. Nat. Rev. Clin. Oncol. 2022, 19, 342–355. [Google Scholar] [CrossRef] [PubMed]
  168. U.S. Food and Drug Administration [press release]. Washington, D.C. (Mar. 26, 2021): FDA approves idecabtagene vicleucel for multiple myeloma. Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-idecabtagene-vicleucel-multiple-myeloma (accessed on 22 August 2023).
  169. Munshi, N.C.; Anderson, L.D., Jr.; Shah, N.; Madduri, D.; Berdeja, J.; Lonial, S.; Raje, N.; Lin, Y.; Siegel, D.; Oriol, A.; et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N. Engl. J. Med. 2021, 384, 705–716. [Google Scholar] [CrossRef]
  170. Rodriguez-Otero, P.; Ailawadhi, S.; Arnulf, B.; Patel, K.; Cavo, M.; Nooka, A.K.; Manier, S.; Callander, N.; Costa, L.J.; Vij, R.; et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N. Engl. J. Med. 2023, 388, 1002–1014. [Google Scholar] [CrossRef]
  171. Bristol Myers Squibb [press release]. Princeton, NJ and Cambridge, MA. (Apr. 17, 2023): Regulatory applications accepted across three regions globally for Abecma for earlier use in adults with triple-class exposed relapsed and/or refractory multiple myeloma. Available online: https://news.bms.com/news/details/2023/Regulatory-Applications-Accepted-Across-Three-Regions-Globally-for-Abecma-for-Earlier-Use-in-Adults-with-Triple-Class-Exposed-Relapsed-andor-Refractory-Multiple-Myeloma/default.aspx (accessed on 19 July 2023).
  172. Berdeja, J.G.; Madduri, D.; Usmani, S.Z.; Jakubowiak, A.; Agha, M.; Cohen, A.D.; Stewart, A.K.; Hari, P.; Htut, M.; Lesokhin, A.; et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): A phase 1b/2 open-label study. Lancet 2021, 398, 314–324. [Google Scholar] [CrossRef]
  173. San-Miguel, J.; Dhakal, B.; Yong, K.; Spencer, A.; Anguille, S.; Mateos, M.V.; Fernández de Larrea, C.; Martínez-López, J.; Moreau, P.; Touzeau, C.; et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N. Engl. J. Med. 2023, 389, 335–347. [Google Scholar] [CrossRef]
  174. Li, C.; Wang, D.; Song, Y.; Huang, H.; Li, J.; Chen, B.; Liu, J.; Dong, Y.; Hu, K.; Liu, P.; et al. CT103A, a novel fully human BCMA-targeting CAR-T cells, in patients with relapsed/refractory multiple myeloma: Updated results of phase 1b/2 study (FUMANBA-1). J. Clin. Oncol. 2023, 41 (Suppl. S16), 8025. [Google Scholar] [CrossRef]
  175. Chen, W.M.; Fu, C.C.; Cai, Z.; Li, Z.H.; Wang, H.J.; Yan, L.Z.; Wu, Y.; Shi, X.L.; Gao, W.; Yan, S.; et al. Sustainable efficacy and safety results from Lummicar study 1: A phase 1/2 study of fully human B-cell maturation antigen-specific CAR T cells (CT053) in Chinese subjects with relapsed and/or refractory multiple myeloma. Blood 2021, 138 (Suppl. S1), 2821. [Google Scholar] [CrossRef]
  176. Biltibo, E.; Berdeja, J.G. State-of-the-Art updates and next questions | BCMA-directed CAR T-Cells: Early results and future directions. Clin. Lymphoma Myeloma Leuk. 2023, 23, 310–321. [Google Scholar] [CrossRef] [PubMed]
  177. Engels, B.; Zhu, X.; Yang, J.; Price, A.; Sohoni, A.; Stein, A.M.; Parent, L.; Greene, M.; Niederst, M.; Whalen, J.; et al. Preservation of T-cell stemness with a novel expansionless CAR-T manufacturing process, which reduces manufacturing time to less than two days, drives enhanced CAR-T cell efficacy. Blood 2021, 138 (Suppl. S1), 2848. [Google Scholar] [CrossRef]
  178. Qu, X.; An, G.; Sui, W.; Wang, T.; Zhang, X.; Yang, J.; Zhang, Y.; Zhang, L.; Zhu, D.; Huang, J.; et al. Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma. J Immunother Cancer 2022, 10, e005145. [Google Scholar] [CrossRef] [PubMed]
  179. Qin, H.; Edwards, J.P.; Zaritskaya, L.; Gupta, A.; Mu, C.J.; Fry, T.J.; Hilbert, D.M.; LaFleur, D.W. Chimeric antigen receptors incorporating D domains targeting CD123 direct potent mono- and bi-specific antitumor activity of T cells. Mol. Ther. 2019, 27, 1262–1274. [Google Scholar] [CrossRef]
  180. Asherie, N.; Kfir-Erenfeld, S.; Avni, B.; Assayag, M.; Dubnikov, T.; Zalcman, N.; Lebel, E.; Zimran, E.; Shaulov, A.; Pick, M.; et al. Development and manufacture of novel locally produced anti-BCMA CAR T cells for the treatment of relapsed/refractory multiple myeloma: Results from a phase I clinical trial. Haematologica 2023, 108, 1827–1839. [Google Scholar] [CrossRef]
  181. Sjöstrand, M.; Sadelain, M. Driving CARs to new places: Locally produced BCMA CAR T cells to treat multiple myeloma. Haematologica 2023, 108, 1721–1723. [Google Scholar] [CrossRef]
  182. Dhodapkar, M.; Alsina, M.; Berdeja, J.; Patel, K.; Vij, R.; Leleu, X.; Truppel-Hartmann, A.; Basudhar, D.; Thompson, E.; Zheng, X.R.; et al. KarMMa-2 cohort 2c: Efficacy and safety of idecabtagene vicleucel in patients with clinical high-risk multiple myeloma due to inadequate response to frontline autologous stem cell transplantation. Blood 2022, 140 (Suppl. S1), 7441–7443. [Google Scholar] [CrossRef]
  183. Usmani, S.; Patel, K.; Hari, P.; Berdeja, J.; Alsina, M.; Vij, R.; Raje, N.; Leleu, X.; Dhodapkar, M.; Reshef, R.; et al. KarMMa-2 cohort 2a: Efficacy and safety of idecabtagene vicleucel in clinical high-risk multiple myeloma patients with early relapse after frontline autologous stem cell transplantation. Blood 2022, 140 (Suppl. S1), 875–877. [Google Scholar] [CrossRef]
  184. Weisel, K.; Mateos, M.V.; Vincent, L.; Martin, T.; Berdeja J, G.; Jakubowiak, A.; Jagannath, S.; Lin, Y.; Thilakarathne, P.; Ghilotti, F.; et al. Comparison of ciltacabtagene autoleucel (cilta-cel) with the current standard of care in triple-exposed multiple myeloma: Adjusted comparison of patient-reported outcomes from CARTITUDE-1 and LOCOMMOTION. Oncology Research and Treatment 2022, 45, 143. [Google Scholar]
  185. Usmani, S.Z.; Martin, T.G.; Berdeja, J.G.; Jakubowiak, A.J.; Agha, M.E.; Cohen, A.D.; Deol, A.; Htut, M.; Lesokhin, A.M.; Munshi, N.C.; et al. Phase 1b/2 study of ciltacabtagene autoleucel, a BCMA-directed CAR-T cell therapy, in patients with relapsed/refractory multiple myeloma (CARTITUDE-1): Two years post-LPI. J. Clin. Oncol. 2022, 40, 8028. [Google Scholar] [CrossRef]
  186. Martin, T.; Krishnan, A.; Yong, K.; Weisel, K.; Mehra, M.; Nair, S.; Qi, K.; Londhe, A.; Diels, J.; Crivera, C.; et al. Comparative effectiveness of ciltacabtagene autoleucel in CARTITUDE-1 versus physician's choice of therapy in the Flatiron Health multiple myeloma cohort registry for the treatment of patients with relapsed or refractory multiple myeloma. EJHaem 2022, 3, 97–108. [Google Scholar] [CrossRef] [PubMed]
  187. Van de Donk, N.; Delforge, M.; Agha, M.; Cohen, A.D.; Cohen, Y.C.; Hillengass, J.; Anguille, S.; Kerre, T.; Roeloffzen, W.; Schecter, J.M.; et al. CARTITUDE-2 cohort B: Efficacy and safety of ciltacabtagene autoleucel, a chimeric antigen receptor T-cell therapy directed against B-cell maturation antigen, in patients with multiple myeloma and early relapse after initial treatment. Br. J. Haematol. 2022, 197, 118–119. [Google Scholar]
  188. van de Donk, N.; Agha, M.E.; Cohen, A.D.; Cohen, Y.C.; Anguille, S.; Kerre, T.; Roeloffzen, W.; Schecter, J.M.; De Braganca, K.C.; Varsos, H.; et al. Biological correlative analyses and updated clinical data of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR-T cell therapy, in patients with multiple myeloma (MM) and early relapse after initial therapy: CARTITUDE-2, cohort B. J. Clin. Oncol. 2022, 40, 8029. [Google Scholar] [CrossRef]
  189. Van de Donk, N.; Agha, M.; Cohen, A.D.; Cohen, Y.C.; Anguille, S.; Kerre, T.; Roeloffzen, W.W.H.; Schecter, J.M.; De Braganca, K.C.; Jackson, C.C.; et al. Ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR-T cell therapy, in patients with multiple myeloma (MM) and early relapse after initial therapy: CARTITUDE-2 cohort B 18-month follow-up. Blood 2022, 140 (Suppl. S1), 7536–7537. [Google Scholar] [CrossRef]
  190. Dytfeld, D.; Dhakal, B.; Agha, M.; Manier, S.; Delforge, M.; Kuppens, S.; Afifi, S.; Deraedt, W.; Taraseviciute-Morris, A.; Schecter, J.M.; et al. Randomised, phase 3 study of bortezomib, lenalidomide and dexamethasone followed by ciltacabtagene autoleucel versus bortezomib, lenalidomide and dexamethasone followed by lenalidomide and dexamethasone maintenance in patients with newly diagnosed multiple myeloma not intended for transplant: CARTITUDE-5. Br. J. Haematol. 2022, 197, 122–123. [Google Scholar]
  191. Boccadoro, M.; San-Miguel, J.; Suzuki, K.; Van de Donk, N.; Cook, G.; Jakubowiak, A.; Madduri, D.; Afifi, S.; Stevens, A.S.; Schecter, J.M.; et al. DVRd followed by ciltacabtagene autoleucel versus DVRd followed by ASCT in patients with newly diagnosed multiple myeloma who are transplant eligible: A randomized phase 3 study (EMagine/CARTITUDE-6). Blood 2022, 140 (Suppl. S1), 4630–4632. [Google Scholar] [CrossRef]
  192. Mi, J.Q.; Zhao, W.H.; Jing, H.M.; Fu, W.J.; Hu, J.D.; Chen, L.J.; Zhang, Y.W.; Yao, D.; Li, H.; Schecter, J.M.; et al. Phase 2, open-label study of ciltacabtagene autoleucel, an anti-BCMA CAR-T cell therapy, in Chinese patients with relapsed/refractory multiple myeloma (CARTIFAN-1): 26-month median follow-up. Blood 2022, 140 (Suppl. S1), 7542–7544. [Google Scholar] [CrossRef]
  193. Zhao, W.H.; Wang, B.Y.; Chen, L.J.; Fu, W.J.; Xu, J.; Liu, J.; Jin, S.W.; Chen, Y.X.; Cao, X.M.; Yang, Y.; et al. Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: A phase 1, single-arm, open-label, multicenter study in China (LEGEND-2). J. Hematol. Oncol. 2022, 15, 86. [Google Scholar] [CrossRef]
  194. Chen, W.M.; Fu, C.C.; Fang, B.J.; Liang, A.B.; Xia, Z.J.; He, Y.J.; Lu, J.; Liu, H.; Hou, M.; Cai, Z.; et al. Phase II study of fully human BCMA-Targeting CAR-T cells (zevorcabtagene autoleucel) in patients with relapsed/refractory multiple myeloma. Blood 2022, 140 (Suppl. S1), 4564–4565. [Google Scholar] [CrossRef]
  195. Kumar, S.K.; Baz, R.C.; Orlowski, R.Z.; Anderson, L.D.; Ma, H.; Shrewsbury, A.; Croghan, K.A.; Bilgi, M.; Kansagra, A.; Kapoor, P.; et al. Results from LUMMICAR-2: A phase 1b/2 study of fully human B-cell maturation antigen-specific CAR T cells (CT053) in patients with relapsed and/or refractory multiple myeloma. Blood 2020, 136 (Suppl. S1), 28–29. [Google Scholar] [CrossRef]
  196. Sperling, A.S.; Derman, B.A.; Nikiforow, S.; Im, S.-Y.; Ikegawa, S.; Prabhala, R.H.; Rodriguez, D.H.; Li, Y.; Quinn, D.S.; Pearson, D.; et al. Updated phase I study results of PHE885, a T-Charge manufactured BCMA-directed CAR-T cell therapy, for patients (pts) with r/r multiple myeloma (RRMM). J. Clin. Oncol. 2023, 41 (16 suppl), 8004. [Google Scholar] [CrossRef]
  197. Arcelix, Inc. [press release]. Redwood, CA (Aug. 14, 2023): Arcellx Announces Partial Clinical Hold Lifted On IMMagine-1 Phase 2 Clinical Program And Reports Second Quarter Financial Results. Available online: https://www.prnewswire.com/news-releases/arcellx-announces-partial-clinical-hold-lifted-on-immagine-1-phase-2-clinical-program-and-reports-second-quarter-financial-results-301900055.html (accessed on 4 September 2023).
  198. Costa, L.J.; Kumar, S.K.; Atrash, S.; Liedtke, M.; Kaur, G.; Derman, B.A.; Bergsagel, P.L.; Mailankody, S.; McCarthy, P.L.; Limones, J.; et al. Results from the first phase 1 clinical study of the B-cell maturation antigen (BCMA) Nex T chimeric antigen receptor (CAR) T cell therapy CC-98633/BMS-986354 in patients (pts) with relapsed/refractory multiple myeloma (RRMM). Blood 2022, 140 (Suppl. S1), 1360–1362. [Google Scholar] [CrossRef]
  199. Du, J.; Fu, W.-J.; Jiang, H.; Dong, B.; Gao, L.; Liu, L.; Ge, J.; He, A.; Li, L.; Lu, J.; et al. Updated results of a phase I, open-label study of BCMA/CD19 dual-targeting fast CAR-T GC012F for patients with relapsed/refractory multiple myeloma (RRMM). J. Clin. Oncol. 2023, 41 (suppl 16), 8005. [Google Scholar] [CrossRef]
  200. Du, J.; Fu, W.J.; Lu, J.; Qiang, W.T.; He, H.Y.; Liu, J.; Yang, Y.; Feng, Z.Y.; Jin, L.N.; Fan, X.Q.; et al. Phase I open-label single-arm study of BCMA/CD19 dual-targeting FasTCAR-T cells (GC012F) as first-line therapy for transplant-eligible newly diagnosed high-risk multiple myeloma. Blood 2022, 140 (Suppl. S1), 889–890. [Google Scholar] [CrossRef]
  201. Du, J.; Jiang, H.; Dong, B.; Gao, L.; Liu, L.; Ge, J.; He, A.; Li, L.; Lu, J.; Chen, X.; et al. Updated results of a multicenter first-in-human study of BCMA/CD19 dual-targeting fast CAR-T GC012F for patients with relapsed/refractory multiple myeloma (RRMM). J. Clin. Oncol. 2022, 40 (suppl 16), 8005. [Google Scholar] [CrossRef]
  202. Gagelmann, N.; Brudno, J. GPRC5D-targeting chimeric antigen receptors: A new treatment for multiple myeloma? The Lancet. Haematology 2023, 10, e82–e83. [Google Scholar] [CrossRef]
  203. Mailankody, S.; Devlin, S.M.; Landa, J.; Nath, K.; Diamonte, C.; Carstens, E.J.; Russo, D.; Auclair, R.; Fitzgerald, L.; Cadzin, B.; et al. GPRC5D-targeted CAR T cells for myeloma. N. Engl. J. Med. 2022, 387, 1196–1206. [Google Scholar] [CrossRef]
  204. Bal, S.; Kocoglu, M.H.; Nadeem, O.; Htut, M.; Gregory, T.; Anderson, L.D.; Costa, L.J.; Buchholz, T.J.; Ziyad, S.; Li, M.; et al. Clinical activity of BMS-986393 (CC-95266), a G protein-coupled receptor class C group 5 member D (GPRC5D)-targeted chimeric antigen receptor (CAR) T cell therapy, in patients with relapsed and/or refractory (R/R) multiple myeloma (MM): First results from a phase 1, multicenter, open-label study. Blood 2022, 140 (Suppl. S1), 883–885. [Google Scholar] [CrossRef]
  205. Zhang, M.; Wei, G.; Zhou, L.; Zhou, J.; Chen, S.; Zhang, W.; Wang, D.; Luo, X.; Cui, J.; Huang, S.; et al. GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma (POLARIS): A first-in-human, single-centre, single-arm, phase 1 trial. The Lancet. Haematology 2023, 10, e107–e116. [Google Scholar] [CrossRef]
  206. Lizana-Vasquez, G.D.; Torres-Lugo, M.; Dixon, R.B.; Powderly, J.D., 2nd; Warin, R.F. The application of autologous cancer immunotherapies in the age of memory-NK cells. Front. Immunol. 2023, 14, 1167666. [Google Scholar] [CrossRef]
  207. Wu, X.; Blackburn, P.R.; Tschumper, R.C.; Ekker, S.C.; Jelinek, D.F. TALEN-mediated genetic tailoring as a tool to analyze the function of acquired mutations in multiple myeloma cells. Blood cancer journal 2014, 4, e210. [Google Scholar] [CrossRef]
  208. Mailankody, S.; Matous, J.V.; Chhabra, S.; Liedtke, M.; Sidana, S.; Oluwole, O.O.; Malik, S.; Nath, R.; Anwer, F.; Cruz, J.C.; et al. Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: Phase 1 UNIVERSAL trial interim results. Nat. Med. 2023, 29, 422–429. [Google Scholar] [CrossRef] [PubMed]
  209. Prieto, J.; Redondo, P.; Lopez-Mendez, B.; D'Abramo, M.; Merino, N.; Blanco, F.J.; Duchateau, P.; Montoya, G.; Molina, R. Understanding the indirect DNA read-out specificity of I-CreI meganuclease. Sci. Rep. 2018, 8, 10286. [Google Scholar] [CrossRef]
  210. Berdeja, J.G.; Martin, T.G.; Rossi, A.; Essell, J.H.; Siegel, D.S.D.; Mailankody, S.; Saini, N.; Holmes, H.; Dhakal, B.; Gasparetto, C.J.; et al. A first-in-human phase 1, multicenter, open-label study of CB-011, a next-generation CRISPR-genome edited allogeneic anti-BCMA immune-cloaked CAR-T cell therapy, in patients with relapsed/refractory multiple myeloma (CaMMouflage trial). J. Clin. Oncol. 2023, 41 (Suppl. 16), TPS8063. [Google Scholar] [CrossRef]
  211. Sommer, C.; Lin, R.; Sutton, J.; Bentley, T.; Nguyen, D.; Yoon, H.; Au, M.; Vargas-Inchaustegui, D.; Cheng, H.Y.; Van Blarcom, T.; et al. Preclinical evaluation of ALLO-605, an allogeneic BCMA Turbocar T (TM) cell therapy for the treatment of multiple myeloma. Blood 2020, 136 (Suppl. S1), 8. [Google Scholar] [CrossRef]
  212. Richter, M.; Cranert, S.; Patil, D.; Zhang, Y.; Tan, Y.N.; Tong, M.; Domingo, C.; Weiss, L.; Marquez, K.; Sparks, J.; et al. P-BCMA-ALLO1-a fully allogeneic stem cell memory T cell (T-SCM) CAR-T therapy targeting BCMA for the treatment of multiple myeloma shows potent anti-tumor activity. Mol. Ther. 2021, 29, 382–383. [Google Scholar]
  213. Amatya, C.; Pegues, M.A.; Lam, N.; Vanasse, D.; Geldres, C.; Choi, S.; Hewitt, S.M.; Feldman, S.A.; Kochenderfer, J.N. Development of CAR T cells expressing a suicide gene plus a chimeric antigen receptor targeting signaling lymphocytic-activation molecule F7. Mol. Ther. 2020, 29, 702–717. [Google Scholar] [CrossRef]
  214. Costello, C.L.; Cohen, A.D.; Patel, K.K.; Ali, S.S.; Berdeja, J.G.; Shah, N.; Ganguly, S.; Kocoglu, M.H.; Abedi, M.; Ostertag, E.M.; et al. Phase 1/2 study of the safety and response of P-BCMA-101 CAR-T cells in patients with relapsed/refractory (R/R) multiple myeloma (MM) (PRIME) with novel therapeutic strategies. Blood 2020, 136 (Suppl. S1), 29–30. [Google Scholar] [CrossRef]
  215. Costello, C.; Derman, B.A.; Kocoglu, M.H.; Deo, A.; Ali, A.A.; Gregory, T.; Dholaria, B.; Berdeja, J.G.; Cohen, A.D.; Patel, K.K.; et al. Clinical trials of BCMA-targeted CAR-T Cells utilizing a novel non-viral transposon system. Blood 2021, 138 (Suppl. S1), 3858. [Google Scholar] [CrossRef]
  216. Korst, C.; Bruins, W.S.C.; Cosovic, M.; Verkleij, C.P.M.; Twickler, I.; Le Clerre, D.; Chion-Sotinel, I.; Zweegman, S.; Galetto, R.; Mutis, T.; et al. Preclinical activity of allogeneic CS1-specific CAR T-Cells (UCARTCS1) in multiple myeloma. Blood 2022, 140 (Suppl. S1), 4215–4216. [Google Scholar] [CrossRef]
  217. Cao, Z.X.; Yang, C.Q.; Wang, Y.F.; Wang, C.; Wang, Q.Y.; Ye, G.; Liu, T.T.; Wang, Q.; Wang, H.Y.; Gong, Y.X.; et al. Allogeneic CAR-NK cell therapy targeting both BCMA and GPRC5D for the treatment of multiple myeloma. Blood 2022, 140 (Suppl. S1), 7378. [Google Scholar] [CrossRef]
  218. Juckett, M.; Mailankody, S.; Eghtedar, A.; Bickers, C.; Zong, X.Y.; Wong, L.; Ly, T.; Byon, J.; Cooley, S.; Valamehr, B.; et al. A phase I study of FT538, an off-the-shelf, multiplexed-engineered, iPSC-derived NK cell therapy in combination with daratumumab in relapsed/refractory multiple myeloma. Blood 2022, 140 (Suppl. S1), 10327–10328. [Google Scholar] [CrossRef]
  219. Xiang, X.; He, Q.; Ou, Y.; Wang, W.; Wu, Y. Efficacy and safety of CAR-modified T cell therapy in patients with relapsed or refractory multiple myeloma: A meta-analysis of prospective clinical trials. Front. Pharmacol. 2020, 11, 544754. [Google Scholar] [CrossRef]
  220. Roex, G.; Timmers, M.; Wouters, K.; Campillo-Davo, D.; Flumens, D.; Schroyens, W.; Chu, Y.; Berneman, Z.N.; Lion, E.; Luo, F.; et al. Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma. J. Hematol. Oncol. 2020, 13, 164. [Google Scholar] [CrossRef] [PubMed]
  221. Mohyuddin, G.R.; Rooney, A.; Balmaceda, N.; Aziz, M.; Sborov, D.W.; McClune, B.; Kumar, S.K. Chimeric antigen receptor T-cell therapy in multiple myeloma: A systematic review and meta-analysis of 950 patients. Blood advances 2021, 5, 1097–1101. [Google Scholar] [CrossRef] [PubMed]
  222. Yang, Q.; Li, X.; Zhang, F.; Yang, Q.; Zhou, W.; Liu, J. Efficacy and safety of CAR-T therapy for relapse or refractory multiple myeloma: A systematic review and meta-analysis. Int. J. Med. Sci. 2021, 18, 1786–1797. [Google Scholar] [CrossRef]
  223. Zhang, L.; Shen, X.; Yu, W.; Li, J.; Zhang, J.; Zhang, R.; Li, J.; Chen, L. Comprehensive meta-analysis of anti-BCMA chimeric antigen receptor T-cell therapy in relapsed or refractory multiple myeloma. Ann. Med. 2021, 53, 1547–1559. [Google Scholar] [CrossRef]
  224. Li, J.; Tang, Y.; Huang, Z. Efficacy and safety of chimeric antigen receptor (CAR)-T cell therapy in the treatment of relapsed and refractory multiple myeloma: A systematic-review and meta-analysis of clinical trials. Transl Cancer Res 2022, 11, 569–579. [Google Scholar] [CrossRef]
  225. Gagelmann, N.; Ayuk, F.A.; Atanackovic, D.; Kroeger, N. B cell maturation antigen-specific CAR T cells for relapsed or refractory multiple myeloma: A meta-analysis. Blood 2019, 134 (Supplement1), 3113. [Google Scholar] [CrossRef]
  226. Gagelmann, N.; Ayuk, F.; Atanackovic, D.; Kroger, N. Outcomes of anti-BCMA CAR T cell therapy for relapsed/refractory multiple myeloma: A meta-analysis. Bone Marrow Transplant. 2020, 55, 130. [Google Scholar]
  227. Gagelmann, N.; Ayuk, F.; Atanackovic, D.; Kroger, N. B cell maturation antigen-specific chimeric antigen receptor T cells for relapsed or refractory multiple myeloma: A meta-analysis. Eur. J. Haematol. 2020, 104, 318–327. [Google Scholar] [CrossRef] [PubMed]
  228. Hu, D.Y.; Chen, L.M.; Yan, D.Q.; Dong, W.L.; Chen, M.; Niu, S.P.; Wang, S.M.; Zhang, J.J.; Nie, X.Y.; Fang, Y. Effectiveness and safety of anti-BCMA chimeric antigen receptor T-cell treatment in relapsed/refractory multiple myeloma: A comprehensive review and meta-analysis of prospective clinical trials. Front. Pharmacol. 2023, 14. [Google Scholar] [CrossRef] [PubMed]
  229. Cron, R.Q.; Goyal, G.; Chatham, W.W. Cytokine storm syndrome. Annu. Rev. Med. 2023, 74, 321–337. [Google Scholar] [CrossRef] [PubMed]
  230. Lee, D.W.; Santomasso, B.D.; Locke, F.L.; Ghobadi, A.; Turtle, C.J.; Brudno, J.N.; Maus, M.V.; Park, J.H.; Mead, E.; Pavletic, S.; et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol. Blood Marrow Transplant. 2019, 25, 625–638. [Google Scholar] [CrossRef]
  231. Chen, G.; Wu, D.; Guo, W.; Cao, Y.; Huang, D.; Wang, H.; Wang, T.; Zhang, X.; Chen, H.; Yu, H.; et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J. Clin. Invest. 2020, 130, 2620–2629. [Google Scholar] [CrossRef]
  232. Le, R.Q.; Li, L.; Yuan, W.; Shord, S.S.; Nie, L.; Habtemariam, B.A.; Przepiorka, D.; Farrell, A.T.; Pazdur, R. FDA approval summary: Tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist 2018, 23, 943–947. [Google Scholar] [CrossRef]
  233. Sharma, S.; Wang, D.N.; Lon, H.K.; Soltantabar, P.; Viqueira, A.; Czibere, A.; Hickman, A.; White, J.L.; Elmeliegy, M. A systematic meta-analysis of cytokine release syndrome incidence in B-cell maturation antigen-targeting chimeric antigen receptor T-cell therapy and bispecific antibodies for patients with relapsed and/or refractory multiple myeloma. Blood 2022, 140 (Suppl. S1), 10036–10038. [Google Scholar] [CrossRef]
  234. Moghanloo, E.; Mollanoori, H.; Talebi, M.; Pashangzadeh, S.; Faraji, F.; Hadjilooei, F.; Mahmoodzadeh, H. Remote controlling of CAR-T cells and toxicity management: Molecular switches and next generation CARs. Transl. Oncol. 2021, 14, 101070. [Google Scholar] [CrossRef]
  235. Yu, S.; Yi, M.; Qin, S.; Wu, K. Next generation chimeric antigen receptor T cells: Safety strategies to overcome toxicity. Mol. Cancer 2019, 18, 125. [Google Scholar] [CrossRef]
  236. Griffioen, M.; van Egmond, E.H.; Kester, M.G.; Willemze, R.; Falkenburg, J.H.; Heemskerk, M.H. Retroviral transfer of human CD20 as a suicide gene for adoptive T-cell therapy. Haematologica 2009, 94, 1316–1320. [Google Scholar] [CrossRef]
  237. Fu, W.J.; Du, J.; Jiang, H.; Cheng, Z.; Wei, R.H.; Yu, K.; Jiang, S.F.; He, F.; Fang, H.L.; Liu, Y.R.; et al. Efficacy and safety of CAR-T therapy with safety switch targeting BCMA for patients with relapsed/refractory multiple myeloma in a phase 1 clinical study. Blood 2019, 134 (Suppl. S1), 3154. [Google Scholar] [CrossRef]
  238. Di Stasi, A.; Tey, S.K.; Dotti, G.; Fujita, Y.; Kennedy-Nasser, A.; Martinez, C.; Straathof, K.; Liu, E.; Durett, A.G.; Grilley, B.; et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 2011, 365, 1673–1683. [Google Scholar] [CrossRef] [PubMed]
  239. Wang, H.; Tang, L.; Kong, Y.; Liu, W.; Zhu, X.; You, Y. Strategies for reducing toxicity and enhancing efficacy of chimeric antigen receptor T cell therapy in hematological malignancies. Int. J. Mol. Sci. 2023, 24. [Google Scholar] [CrossRef] [PubMed]
  240. Vaddepally, R.K.; Kharel, P.; Pandey, R.; Garje, R.; Chandra, A.B. Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. Cancers (Basel) 2020, 12, 738. [Google Scholar] [CrossRef] [PubMed]
  241. Meermeier, E.W.; Bergsagel, P.L. Revisiting checkpoint inhibitors for myeloma: Maintenance after stem cell transplant. J. Clin. Invest. 2023, 133, e167346. [Google Scholar] [CrossRef]
  242. Skarbnik, A.P.; Donato, M.L.; Feinman, R.; Rowley, S.D.; Vesole, D.H.; Goy, A.H.; Munshi, P.N.; Feldman, T.; Leslie, L.A.; Biran, N.; et al. Safety and efficacy of consolidation therapy with ipilimumab plus nivolumab after autologous stem cell transplantation. Transplant Cell Ther 2021, 27, 391–403. [Google Scholar] [CrossRef]
  243. Usmani, S.Z.; Schjesvold, F.; Oriol, A.; Karlin, L.; Cavo, M.; Rifkin, R.M.; Yimer, H.A.; LeBlanc, R.; Takezako, N.; McCroskey, R.D.; et al. Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): A randomised, open-label, phase 3 trial. The Lancet. Haematology 2019, 6, e448–e458. [Google Scholar] [CrossRef]
  244. Mateos, M.V.; Blacklock, H.; Schjesvold, F.; Oriol, A.; Simpson, D.; George, A.; Goldschmidt, H.; Larocca, A.; Chanan-Khan, A.; Sherbenou, D.; et al. Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): A randomised, open-label, phase 3 trial. The Lancet. Haematology 2019, 6, e460–e469. [Google Scholar] [CrossRef]
  245. U.S. Food and Drug Administration [press release]. Washington, D.C. (Sept. 20, 2017): FDA alerts healthcare professionals and oncology clinical investigators about two clinical trials on hold evaluating KEYTRUDA® (pembrolizumab) in patients with multiple myeloma. Available online: https://www.fda.gov/drugs/drug-safety-and-availability/fda-alerts-healthcare-professionals-and-oncology-clinical-investigators-about-two-clinical-trials (accessed on 10 August 2023).
  246. Lesokhin, A.M.; Ansell, S.M.; Armand, P.; Scott, E.C.; Halwani, A.; Gutierrez, M.; Millenson, M.M.; Cohen, A.D.; Schuster, S.J.; Lebovic, D.; et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: Preliminary results of a phase 1b study. J. Clin. Oncol. 2016, 34, 2698–2704. [Google Scholar] [CrossRef]
  247. Schjesvold, F.; Paiva, B.; Ribrag, V.; Rodriguez-Otero, P.; San-Miguel, J.F.; Robak, P.; Hansson, M.; Onishi, M.; Hamidi, H.; Malhi, V.; et al. Cobimetinib alone and plus venetoclax with/without atezolizumab in patients with relapsed/refractory multiple myeloma. Clin. Lymphoma Myeloma Leuk. 2022, 23, e59–e70. [Google Scholar] [CrossRef]
  248. Lesokhin, A.; LeBlanc, R.; Dimopoulos, M.A.; Capra, M.; Carlo-Stella, C.; Karlin, L.; Castilloux, J.F.; Forsberg, P.; Parmar, G.; Tosikyan, A.; et al. Isatuximab in combination with cemiplimab in patients with relapsed/refractory multiple myeloma: A phase 1/2 study. Cancer medicine 2023, 12, 10254–10266. [Google Scholar] [CrossRef]
  249. Weiskopf, K. Cancer immunotherapy targeting the CD47/SIRPα axis. Eur. J. Cancer 2017, 76, 100–109. [Google Scholar] [CrossRef] [PubMed]
  250. Sun, J.; Muz, B.; Alhallak, K.; Markovic, M.; Gurley, S.; Wang, Z.; Guenthner, N.; Wasden, K.; Fiala, M.; King, J.; et al. Targeting CD47 as a novel immunotherapy for multiple myeloma. Cancers (Basel) 2020, 12, 305. [Google Scholar] [CrossRef] [PubMed]
  251. Paul, B.; Liedtke, M.; Khouri, J.; Rifkin, R.; Gandhi, M.D.; Kin, A.; Levy, M.Y.; Silbermann, R.; Cottini, F.; Sborov, D.W.; et al. A phase II multi-arm study of magrolimab combinations in patients with relapsed/refractory multiple myeloma. Future Oncol. 2023, 19, 7–17. [Google Scholar] [CrossRef]
  252. Wilson, W.C.; Richards, J.; Puro, R.J.; Andrejeva, G.; Capoccia, B.J.; Donio, M.J.; Hiebsch, R.R.; Chakraborty, P.; Sung, V.; Pereira, D.S. AO-176, a highly differentiated clinical stage anti-CD47 antibody, exerts potent anti-tumor activity in preclinical models of multiple myeloma as a single agent and in combination with approved therapeutics. Blood 2020, 136 (Suppl. S1), 3–4. [Google Scholar] [CrossRef]
  253. Chung, A.; Huang, C.Y.; Martin, T.; Wolf, J.L.; Wong, S.W.; Shah, N. Phase II study of pembrolizumab in multiple myeloma patients relapsing after or refractory to anti-BCMA CAR-T therapies. Blood 2022, 140 (Suppl. S1), 12651–12652. [Google Scholar] [CrossRef]
  254. Biran, N.; Gourna Paleoudis, E.; Feinman, R.; Vesole, D.H.; Zenreich, J.; Wang, S.; Ahn, J.; Bansal, M.; Rowley, S.; Donato, M.; et al. Pembrolizumab, lenalidomide and dexamethasone post autologous transplant in patients with high-risk multiple myeloma. Am. J. Hematol. 2021, 96, E430–E433. [Google Scholar] [CrossRef]
  255. Cho, H.J.; Bekri, S.; Wong, S.; Raval, A.; Groeniger, W.; Kim-Schulze, S.; Xie, H.; Fritsch, E.W.; Hamidi, H. Multi-omic analysis of the tumor microenvironment reveals novel associations in a clinical trial of atezolizumab +/- daratumumab for relapsed/refractory multiple myeloma. Clinical Lymphoma Myeloma & Leukemia 2021, 21, S78. [Google Scholar]
  256. Paul, B.; Liedtke, M.; Monge, J.; Chaudhry, M.; Rifkin, R.M.; Gandhi, M.D.; Khouri, J.; Kin, A.; Kovacsovics, T.; Levy, M.Y.; et al. A phase 2 multi-arm study of magrolimab combinations in patients with relapsed/refractory multiple myeloma. Blood 2021, 138 (Suppl. S1), 2757. [Google Scholar] [CrossRef]
  257. Ojo, A.S.; Araoye, M.O.; Ali, A.; Sarma, R. The impact of current therapeutic options on the health-related quality of life of patients with relapse/refractory multiple myeloma: A systematic review of clinical studies. J. Cancer Surviv. Published online ahead of print. 2023. [Google Scholar] [CrossRef]
  258. Elbezanti, W.O.; Challagundla, K.B.; Jonnalagadda, S.C.; Budak-Alpdogan, T.; Pandey, M.K. Past, present, and a glance into the future of multiple myeloma treatment. Pharmaceuticals (Basel) 2023, 16, 415. [Google Scholar] [CrossRef]
  259. Ali, S.A.; Shi, V.; Maric, I.; Wang, M.; Stroncek, D.F.; Rose, J.J.; Brudno, J.N.; Stetler-Stevenson, M.; Feldman, S.A.; Hansen, B.G.; et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 2016, 128, 1688–1700. [Google Scholar] [CrossRef] [PubMed]
  260. Cohen, A.D.; Garfall, A.L.; Stadtmauer, E.A.; Melenhorst, J.J.; Lacey, S.F.; Lancaster, E.; Vogl, D.T.; Weiss, B.M.; Dengel, K.; Nelson, A.; et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J. Clin. Invest. 2019, 129, 2210–2221. [Google Scholar] [CrossRef]
  261. Cohen, A.D.; Garfall, A.L.; Stadtmauer, E.A.; Lacey, S.F.; Lancaster, E.; Vogl, D.T.; Weiss, B.M.; Ambrose, D.E.; Nelson, A.M.; Chen, F.; et al. Safety and efficacy of B-cell maturation antigen (BCMA)-specific chimeric antigen receptor T cells (CART-BCMA) with cyclophosphamide conditioning for refractory multiple myeloma (MM). Blood 2017, 130 (Suppl. S1), 505. [Google Scholar] [CrossRef]
  262. Green, D.J.; Pont, M.; Sather, B.D.; Cowan, A.J.; Turtle, C.J.; Till, B.G.; Nagengast, A.M.; Libby, I., E. N., ; Becker, P.S.; Coffey, D.G.; et al. Fully human BCMA targeted chimeric antigen receptor T cells administered in a defined composition demonstrate potency at low doses in advanced stage high risk multiple myeloma. Blood 2018, 132 (Suppl. S1), 1011. [Google Scholar] [CrossRef]
  263. Hamieh, M.; Dobrin, A.; Cabriolu, A.; van der Stegen, S.J.C.; Giavridis, T.; Mansilla-Soto, J.; Eyquem, J.; Zhao, Z.; Whitlock, B.M.; Miele, M.M.; et al. CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape. Nature 2019, 568, 112–116. [Google Scholar] [CrossRef]
  264. Simoes, R.D.; Shirasaki, R.; Downey-Kopyscinski, S.L.; Matthews, G.; Yiguo, H.; Sheffer, M.; Dhimolea, E.; Dashevsky, O.; Gandolfi, S.; Dempster, J.; et al. Systematic characterization of genes representing preferential molecular vulnerabilities for myeloma cells compared to other neoplasias - implications for the biology and therapeutic targeting of myeloma. Blood 2019, 134 (Suppl. S1), 4407. [Google Scholar] [CrossRef]
  265. van der Schans, J.J.; van de Donk, N.; Mutis, T. Dual targeting to overcome current challenges in multiple myeloma CAR T-cell treatment. Front. Oncol. 2020, 10, 1362. [Google Scholar] [CrossRef]
  266. de Larrea, C.F.; Staehr, M.; Lopez, A.V.; Ng, K.Y.; Chen, Y.; Godfrey, W.D.; Purdon, T.J.; Ponomarev, V.; Wendel, H.G.; Brentjens, R.J.; et al. Defining an optimal dual-targeted CAR T-cell therapy approach simultaneously targeting BCMA and GPRC5D to prevent BCMA escape-driven relapse in multiple myeloma. Blood Cancer Discov 2020, 1, 146–154. [Google Scholar] [CrossRef]
  267. Smith, E.L.; Harrington, K.; Staehr, M.; Masakayan, R.; Jones, J.; Long, T.J.; Ng, K.Y.; Ghoddusi, M.; Purdon, T.J.; Wang, X.; et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci. Transl. Med. 2019, 11. [Google Scholar] [CrossRef]
  268. Holthof, L.C.; Mutis, T. Challenges for immunotherapy in multiple myeloma: Bone marrow microenvironment-mediated immune suppression and immune resistance. Cancers (Basel) 2020, 12, 988. [Google Scholar] [CrossRef] [PubMed]
  269. Wijnands, C.; Noori, S.; Donk, N.; VanDuijn, M.M.; Jacobs, J.F.M. Advances in minimal residual disease monitoring in multiple myeloma. Crit. Rev. Clin. Lab. Sci. 2023, 1–17. [Google Scholar] [CrossRef] [PubMed]
Table 1. Selected Trials of Belantamab Mafodotin in Multiple Myeloma (MM).
Table 1. Selected Trials of Belantamab Mafodotin in Multiple Myeloma (MM).
Trial ID (References) Drugs Phase Enrollment (N) Trial Title
NCT02064387 [55] BelMaf I 79 Open-Label, Dose Escalation Study To Investigate The Safety, Pharmacokinetics, Pharmacodynamics, Immunogenicity And Clinical Activity Of The Antibody Drug Conjugate GSK2857916 In Subjects With RRMM And Other Advanced Hematologic Malignancies Expressing BCMA (DREAMM -1)
NCT03525678 [53,56,57,58] BelMaf II 221 Open Label, Randomized, Two-Arm Study To Investigate The Efficacy And Safety Of Two Doses Of The Antibody Drug Conjugate GSK2857916 In Participants With MM Who Had 3 Or More Prior Lines Of Treatment, Are Refractory To A Proteasome Inhibitor And An Immunomodulatory Agent And Have Failed An Anti-CD38 Antibody (DREAMM-2)
NCT04162210 [59] BelMaf vs (Pom + Dex) III 180 Open-Label, Randomized Study To Evaluate The Efficacy And Safety Of Single Agent Belantamab Mafodotin Compared To Pomalidomide Plus Low Dose Dexamethasone In Participants With RRMM (DREAMM-3)
NCT03848845 [60] BelMaf + Pembro I/II 41 Single Arm Open-Label Study To Explore Safety And Clinical Activity Of GSK2857916 Administered In Combination With Pembrolizumab In Subjects With RRMM (DREAMM-4)
NCT04126200 [50,61,62] BelMaf + Various I/II 464 Randomized, Open-label Platform Study Utilizing a Master Protocol to Study Belantamab Mafodotin (GSK2857916) as Monotherapy and in Combination With Anti-Cancer Treatments in Participants With RRMM - DREAMM-5
NCT03544281 [63,64,65] BelMaf + Dex + (Len or Bort) I/II 152 Open-Label, Dose Escalation And Expansion Study To Evaluate Safety, Tolerability, And Clinical Activity Of GSK2857916 Administered In Combination With Lenalidomide Plus Dexamethasone, Or Bortezomib Plus Dexamethasone In Participants With RRMM (DREAMM-6)
NCT04246047 [66,67] Bort + Dex + (BelMaf or Dara) III 478 Multicenter, Open-Label, Randomized Study To Evaluate The Efficacy And Safety Of The Combination Of Belantamab Mafodotin, Bortezomib, And Dexamethasone Compared With The Combination Of Daratumumab, Bortezomib, And Dexamethasone In Participants With RRMM (DREAMM-7)
NCT04484623 [68,69] Pom + Dex + (BelMaf or Bort) III 450 Multicenter, Open-Label, Randomized Study To Evaluate The Efficacy And Safety Of Belantamab Mafodotin In Combination With Pomalidomide And Dexamethasone Versus Pomalidomide Plus Bortezomib And Dexamethasone In Participants With RRMM (DREAMM-8)
NCT04091126 [70,71,72] Bort + Len + Dex (± BelMaf) I 144 Randomized, Dose And Schedule Evaluation Study To Investigate The Safety, Pharmacokinetics, Pharmacodynamics And Clinical Activity Of Belantamab Mafodotin Administered In Combination With Standard Of Care In Participants With NDMM (DREAMM-9)
NCT05064358 [73] BelMaf II 180 Randomized, Parallel, Open-label Study to Investigate the Safety, Efficacy, and Pharmacokinetics of Various Dosing Regimens of Single-agent Belantamab Mafodotin (GSK2857916) in Participants With RRMM (DREAMM-14)
BelMaf = belantamab mafodotin; Bort = bortezomib; Dara, = daratumumab; Dex = dexamethasone; Len = lenalidomide; MM = multiple myeloma; NDMM = newly diagnosed MM; Pembro = pembrolizumab; Pom = pomalidomide. RRMM = relapsed and/or refractory MM.
Table 2. Non-BCMA-directed ADCs in Active Clinical Trials for RRMM.
Table 2. Non-BCMA-directed ADCs in Active Clinical Trials for RRMM.
Drug Target Trial ID (References) Payload
STI-6129 CD38 NCT05308225 [83] Duostatin-5.2 (MMAF derivative; tubulin inhibitor)
Modakafusp alfa (TAK-573) CD38 NCT03215030 [84] Interferon alfa 2b (attenuated form)
MT-169 (TAK-169) CD38 NCT04017130 [85] Ribosome-inactivating Shiga-like toxin-A subunit
FOR46 CD46 NCT03650491 [86] MMAE
Indatuximab ravtansine (BT-062) CD138 NCT01638936 [87] DM4 (anti-tubulin maytansinoid)
LM-305 GPRC5D NCT05647512 [88] NA
STRO-001 CD74 NCT03424603 [89,90] Maytansinoid (chemistry not disclosed)
MMAE = monomethylauristatin E; MMAF = monomethylauristatin F; NA = information not available.
Table 3. Selected Trials of Teclistamab in Multiple Myeloma (MM).
Table 3. Selected Trials of Teclistamab in Multiple Myeloma (MM).
Trial ID (References) Drugs Phase Enrollment (N) Trial Title
NCT04557098 [97,98,99,100] Tec I/II 244 First-in-Human, Open-Label, Dose Escalation Study of Teclistamab in Subjects With RRMM (MajesTEC-1)
NCT03145181 [101] Tec iv vs. Tec sc I 282 First-in-Human, Open-Label, Dose Escalation Study of Teclistamab, a Humanized BCMA x CD3 Bispecific Antibody in Subjects With RRMM (MajesTEC-1)
NCT04722146 [102,103] Tec in various combinations with anti-myeloma agents Ib 140 A Multi-arm Study of Teclistamab With Other Anticancer Therapies in Participants With MM (MajesTEC-2)
NCT05083169 [104] (Dara + Tec) vs. (Dara + Pom + Bort + Dex) III 560 Randomized Study Comparing Teclistamab in Combination With Daratumumab SC (Tec-Dara) Versus Daratumumab SC, Pomalidomide, and Dexamethasone (DPd) or Daratumumab SC, Bortezomib, and Dexamethasone (DVd) in Participants With RRMM (MajesTEC-3)
NCT05243797 [105] (Tec +/- Len) vs. Len III 1500 Teclistamab in Combination With Lenalidomide and Teclistamab Alone Versus Lenalidomide Alone in Participants With NDMM as Maintenance Therapy Following Autologous Stem Cell Transplantation - MajesTEC-4
NCT05552222 [106] Tec + Dara + Len vs. Dara + Len +Dex III 1060 Randomized Study Comparing Teclistamab in Combination With Daratumumab SC and Lenalidomide (Tec-DR) Versus Daratumumab SC, Lenalidomide, and Dexamethasone (DRd) in Participants With NDMM Who Are Either Ineligible or Not Intended for Autologous Stem Cell Transplant as Initial Therapy (MajesTEC-7)
NCT05572515 Tec vs. (Pom + Bort + Dex or Carf + Dex) III 590 Randomized Study Comparing Teclistamab Monotherapy Versus Pomalidomide, Bortezomib, Dexamethasone (PVd) or Carfilzomib, Dexamethasone (Kd) in Participants With RRMM Who Have Received 1 to 3 Prior Lines of Therapy, Including an Anti-CD38 Monoclonal Antibody and Lenalidomide (MajesTEC-9)
NCT04586426 Tec + Tal + Dara I/II 164 Dose Escalation Study of the Combination of the Bispecific T Cell Redirection Antibodies Talquetamab and Teclistamab in Participants With RRMM (RedirecTT-1)
NCT04108195 [107,108] (Dara + Tec +/- Pom) vs. (Dara + Tal +/- Pom) I 295 Study of Subcutaneous Daratumumab Regimens in Combination With Bispecific T Cell Redirection Antibodies for the Treatmentof Subjects With MM (TRIMM-2)
NCT05338775 Tec + Tal + “PD-1 inhibitor” Ib 152 Study of Bispecific T Cell Redirection Antibodies in Combination With Checkpoint Inhibition for the Treatment of Participants With RRMM (TRIMM-3)
Bort = bortezomib; Carf = carfilzomib; Dara = daratumumab; Dex = dexamethasone; Len = lenalidomide; MM = multiple myeloma; NDMM = newly diagnosed MM; Pom = pomalidomide; RRMM = relapsed and/or refractory MM; Tal = talquetamab; Tec = teclistamab. .
Table 4. Selected Trials of Elranatamab in Multiple Myeloma (MM).
Table 4. Selected Trials of Elranatamab in Multiple Myeloma (MM).
Trial ID (References) Drugs Phase Enrollment (N) Trial Title
NCT03269136 [111,112] Elran + (Dex or Len or Pom) I 101 Open Label Study To Evaluate The Safety, Pharmacokinetic, Pharmacodynamic And Clinical Activity Of Elranatamab (PF-06863135), A B-Cell Maturation Antigen (BCMA) X CD3 Bispecific Antibody, As A Single Agent And In Combination With Immunomodulatory Agents In Patients With RRMM (MagnetisMM-1)
NCT04649359 [110] Elran II 187 Open-Label, Multicenter, Non-Randomized Study Of Elranatamab (Pf-06863135) Monotherapy In Participants With MM Who Are Refractory To At Least One Proteasome Inhibitor, One Immunomodulatory Drug And One Anti-CD38 Antibody (MagnetisMM-3)
NCT05090566 [113] (Elran + Niro) vs. (Elran + Len + Dex) II 105 Open Label Umbrella Study Of Elranatamab (PF-06863135), A B-Cell Maturation Antigen (BCMA) CD3 Bispecific Antibody, In Combination With Other Anti-Cancer Treatments In Participants With MM (MagnetisMM-4)
NCT05020236 [114,115] Elran vs. (Elran + Dara) vs. (Dara + Pom + Dex) III 589 Open-Label, 3-Arm, Multicenter, Randomized Study To Evaluate The Efficacy And Safety Of Elranatamab (PF-06863135) Monotherapy And Elranatamab + Daratumumab Versus Daratumumab + Pomalidomide + Dexamethasone In Participants With RRMM Who Have Received At Least 1 Prior Line Of Therapy Including Lenalidomide And A Proteasome Inhibitor (MagnetisMM-5)
NCT05623020 (Elran + Dara + Len) vs (Dara + Len + Dex) III 966 Open-Label, 2-Arm, Multicenter, Randomized Study To Evaluate The Efficacy And Safety Of Elranatamab (PF-06863135) + Daratumumab + Lenalidomide Versus Daratumumab + Lenalidomide + Dexamethasone In Transplant-Ineligible Participants With NDMM (MagnetisMM-6)
NCT05317416 [116] Elran vs. Len III 760 Randomized, 2-Arm Study Of Elranatamab (PF-06863135) Versus Lenalidomide In Patients NDMM After Undergoing ASCT (MagnetisMM-7)
NCT05014412 Elran vs. Elran + Dex I/II 76 Open-Label, Multicenter Study To Evaluate A Dosing Regimen With Two Step-Up Priming Doses And Longer Dosing Intervals Of Elranatamab (PF-06863135) Monotherapy In Participants With RRMM (MagnetisMM-9)
ASCT = autologous stem cell transplantation; Dara = daratumumab; Dex = dexamethasone; Elran = elranatamab; Len = lenalidomide; MM = multiple myeloma; NDMM = newly diagnosed MM; Niro = nirogacestat; Pom = pomalidomide; RRMM = relapsed and/or refractory MM.
Table 6. Selected Trials of Talquetamab in Multiple Myeloma (MM).
Table 6. Selected Trials of Talquetamab in Multiple Myeloma (MM).
Trial ID (References) Drugs Phase Enrollment (N) Trial Title
NCT05050097 (Tal + Carf +/- Dara) vs. (Tal + Len +/- Dara) vs. (Tal + Pom) I 182 Multi-arm Study of Talquetamab With Other Anticancer Therapies in Participants With MM (MonumenTAL-2)
NCT05455320 [136] (Dara + Pom + Dex +/- Tal) vs. (Dara + Dex + Tal) III 810 Randomized Study Comparing Talquetamab in Combination With Daratumumab (SC) and Pomalidomide (Tal-DP) or Talquetamab (SC) in Combination With Daratumumab SC (Tal-D) Versus Daratumumab SC, Pomalidomide and Dexamethasone (DPd), in Participants With RRMM Who Have Received at Least 1 Prior Line of Therapy (MonumenTAL-3)
NCT04586426 Tal + Tec +/- Dara I/II 184 Dose Escalation Study of the Combination of the Bispecific T Cell Redirection Antibodies Talquetamab and Teclistamab in Participants With RRMM
NCT05338775 Tal + Tec + PD-1 inhibitor I 152 Study of Bispecific T Cell Redirection Antibodies in Combination With Checkpoint Inhibition for the Treatment of Participants With RRMM
NCT04634552/ NCT03399799 [137,138,139,140,141] Tal I/II 320 First-in-Human, Open-Label, Dose Escalation Study of Talquetamab, a Humanized GPRC5D x CD3 Bispecific Antibody, in Subjects With RRMM (MonumenTAL-1)
NCT04108195 [142,143] (Dara + Tal +/- Pom) vs. (Dara + Tec +/- Pom) I 294 Study of Subcutaneous Daratumumab Regimens in Combination With Bispecific T Cell Redirection Antibodies for the Treatment of Subjects With MM (TRIMM-2)
Carf = carfilzomib; Dara = daratumumab; Dex = dexamethasone; Len = lenalidomide; Pom = pomalidomide; RRMM = relapsed and/or refractory multiple myeloma; MM = multiple myeloma; Tal = talquetamab; Tec = teclistamab .
Table 7. Selective Active Trials of Cevostamab in Multiple Myeloma (MM).
Table 7. Selective Active Trials of Cevostamab in Multiple Myeloma (MM).
Trial ID (References) Drugs Phase Enrollment (N) Trial Title
NCT05801939 Cev II 30 Study of Cevostamab Consolidation Following BCMA CAR T Cell Therapy for RRMM
NCT05646836 Cev + Toc +/- XmAb24306 I 90 Open-label, Multicenter Dose-escalation Study to Evaluate the Safety, Pharmacokinetics, and Activity of XmAb24306 in Combination With Cevostamab in Patients With RRMM
NCT03275103 [148,149] Cev +/- Toc I 420 Open-Label, Multicenter Trial Evaluating the Safety and Pharmacokinetics of Escalating Doses of Cevostamab (BFCR4350A) in Patients With RRMM (CAMMA-3; GO39775)
NCT05535244 Cev + Toc I/II 140 Open-Label, Multi-Cohort Study to Evaluate the Efficacy and Safety of Cevostamab in Prior B Cell Maturation Antigen-Exposed Patients With RRMM (CAMMA-2)
NCT04910568 [150] Cev + Toc + Dex + (Dara or Pom) I 184 Open-Label, Multicenter Trial Evaluating the Safety, Pharmacokinetics, and Activity of Cevostamab as Monotherapy and Cevostamab Plus Pomalidomide and Dexamethasone or Cevostamab Plus Daratumumab and Dexamethasone in Patients With RRMM (CAMMA-1)
Cev = cevostamab; Dara = daratumumab; Dex = dexamethasone; Pom = pomalidomide; RRMM = relapsed and/or refractory multiple myeloma; Toc = tocilizumab.
Table 9. Meta-analytic Studies of Randomized Controlled Trials of BCMA-Targeted CAR T-cells for RRMM.
Table 9. Meta-analytic Studies of Randomized Controlled Trials of BCMA-Targeted CAR T-cells for RRMM.
Efficacy Toxicity
Reference No. of Trials Total No. of Patients Pooled ORR Pooled CRR Pooled MRD Negativity Median PFS (Months) CRS > Grade 3 Neurotoxicity (ICANS/CRES)
[219] 27 497 89% 13% 81% NR 76% 8%
[220] 27 630 80.5% 71.9% 28a/68b 12.2 14.1% 20.4a/1.8b
[221] 30 950 78.3% NR NR NR 6.4 3.5%
[222] 23 350 77% 37% 78% 8 14% 13%
[223] 22 681 85.2 47.0% 97.8% 14.0 6.6% 2.2%
[224] 10 353 NR 55% NR NR 8.0% NR
[225] 15 285 82% 38% 77% 10 15 18
[226] 20 447 84% 36% 83% 10 15% 17%
[227] 15 285 82% 36% 77% 10 15% 18%
[228] 21 761 87% 44% 78% 8.77 11% 10%
CRES = CAR T-cell-related encephalopathy syndrome; CRR = complete response rate; CRS = cytokine release syndrome; ICANS = immune effector cell–associated neurotoxicity syndrome; MRD = minimal residual disease; ORR = overall response rate; PFS = progression-free survival. a Lymphodepletion with cyclophosphamide/fludarabine; b Lymphodepletion with cyclophosphamide.
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